EP1441735B1 - Inhibiteurs de l'integrase du vih a base d'hydroxypyrimidinone carboxamide n-substitue - Google Patents

Inhibiteurs de l'integrase du vih a base d'hydroxypyrimidinone carboxamide n-substitue Download PDF

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Publication number
EP1441735B1
EP1441735B1 EP02801950A EP02801950A EP1441735B1 EP 1441735 B1 EP1441735 B1 EP 1441735B1 EP 02801950 A EP02801950 A EP 02801950A EP 02801950 A EP02801950 A EP 02801950A EP 1441735 B1 EP1441735 B1 EP 1441735B1
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Prior art keywords
alkyl
oxo
methyl
hydroxy
carboxamide
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EP1441735A1 (fr
Inventor
Benedetta Irbm Crescenzi
Cristina Irbm Gardelli
Ester Irbm Muraglia
Emanuela Irbm Nizi
Federica Irbm Orvieto
Paola Irbm Pace
Giovanna Irbm Pescatore
Alessia Irbm Petrocchi
Marco Irbm Poma
Michael Irbm Rowley
Rita Irbm Scarpelli
Vincenzo Irbm Summa
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Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
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Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention is directed to N-substituted 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides and pharmaceutically acceptable salts thereof, their synthesis, and their use as inhibitors of the HIV integrase enzyme.
  • the compounds and pharmaceutically acceptable salts thereof of the present invention are useful for preventing or treating infection by HIV and for treating or delaying the onset of AIDS.
  • a retrovirus designated human immunodeficiency virus is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
  • This virus was previously known as LAV, HTLV-III, or ARV.
  • a common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells.
  • Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site.
  • the fourth step in the process, repair synthesis of the resultant gap may be accomplished by cellular enzymes.
  • Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)].
  • Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4,1267 (1985); Power, M.D. et al., Science, 231 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.
  • antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhbitors such as indinavir and nelfinavir.
  • the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication.
  • the inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HIV infected cells.
  • the particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication.
  • the present invention is directed to novel hydroxypyrimidinone carboxamides. These compounds are useful in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV and in the prevention, treatment, and delay in the onset of AIDS and/or ARC, either as compounds or their pharmaceutically acceptable salts or hydrates (when appropriate), or as pharmaceutical composition ingredients, whether or not in combination with other HIV/AIDS antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention includes a compound of Formula (I): wherein
  • the present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions.
  • the compounds of the present invention can be used in methods of treating AIDS, methods of delaying the onset of AIDS, methods of preventing AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV.
  • the present invention includes the N-substituted hydroxypyrimidinone carboxamides of Formula (I) above. These compounds and pharmaceutically acceptable salts thereof are HIV integrase inhibitors.
  • An embodiment of the present invention is a compound of Formula (I) exactly as defined above, except that in the definition of R k , R k is optionally substituted with one or more substituents each of which is independently one of the substituents (1) to (18), and is optionally mono-substituted with one of the substituents (19) to (34).
  • R 1 is one of substitutents (1) to (16) and in the definition of R k , R k is optionally substituted with one or more substituents (e.g., optionally from 1 to 7, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2 substituents, or is optionally monosubstituted) each of which is independently one of substitutents (1) to (31).
  • substituents e.g., optionally from 1 to 7, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2 substituents, or is optionally monosubstituted
  • Another embodiment of the present invention is a compound of Formula (I), wherein R 1 is:
  • R 1 is one of groups (1) to (16).
  • Another embodiment of the present invention is a compound of Formula (I), wherein R 1 is:
  • R 1 is one of groups (1) to (5).
  • Another embodiment of the present invention is a compound of Formula (I), wherein R 1 is:
  • R 1 is one of groups (1) to (5).
  • R k is C 3-8 cycloalkyl; aryl selected from phenyl and naphthyl; a bicyclic carbocycle selected from indanyl and tetrahydronaphthyl; a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; or a bicyclic heterocycle which is a benzene ring fused to a 5- or 6-membered saturated or unsaturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S; wherein the cycloalkyl, aryl, bicyclic carbocycle, saturated heterocyclic ring, heteroaromatic ring, or bicyclic heterocycle is optionally substituted with from 1 to 4 substituents each of which is independently
  • the cycloalkyl, aryl, bicyclic carbocycle, saturated heterocyclic ring, heteroaromatic ring, or bicyclic heterocycle is optionally substituted with from 1 to 4 substituents each of which is independently selected from the groups (1) to (27).
  • R k i.e., the cycloalkyl, aryl, bicyclic carbocycle, saturated heterocyclic ring, heteroaromatic ring, or bicyclic heterocycle
  • R k is optionally substituted with from 1 to 4 substituents each of which is independently one of the substituents (1) to (19), and is optionally mono-substituted with one of the substituents (20) to (28).
  • R k is optionally substituted with from 1 to 4 substituents each of which is independently one of the substituents (1) to (19), and is mono-substituted with one of the substituents (20) to (28).
  • each R m is independently C 3-7 cycloalkyl; aryl selected from phenyl and naphthyl; a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein any N is optionally oxidized to form an N-oxide; or a bicyclic heterocycle which is a benzene ring fused to a 5- or 6-membered, saturated or unsaturated heterocyclic ring containing from 1 to 3 heteroatoms selected from N, O and S; wherein the cycloalkyl or the aryl defined in R m is optionally substituted with from 1 to 4 substituents each of which is independently halogen, -C 1-4 alkyl, -C 1-4 haloalkyl, -O-C 1-4 alkyl, -O-
  • R k is phenyl; a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from 1 or 2 N atoms, 0 or 10 atoms, and 0 or 1 S atoms; a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from 1 or 2 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms; or a bicyclic heterocycle which is a benzene ring fused to a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms; and all other variables are as originally defined; or a pharmaceutically acceptable salt thereof.
  • each R m is independently cyclopropyl; phenyl; a 5- or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl; or a 5- or 6-membered heteroaromatic ring selected from thienyl, pyridyl optionally in the form of an N-oxide, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, and pyridazinyl; wherein the cyclopropyl is unsubstituted; the phenyl is optionally
  • Another embodiment of the present invention is a compound of Formula (I), wherein R 2 is:
  • Another embodiment of the present invention is a compound of Formula (I) exactly as defined in the immediately preceding embodiment, except that when R 2 is -C 1-6 alkyl substituted with -N(R a R b ), it is with the proviso that -N(R a R b ) is not attached to the carbon atom in the -C 1-6 alkyl group that is attached to the ring nitrogen (i.e., that the -N(R a R b ) group is not attached to the carbon atom alpha to the ring nitrogen).
  • Another embodiment of the present invention is a compound of Formula (I), wherein R 2 is methyl; and all other variables are as originally defined above; or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention is a compound of Formula (I), wherein R 3 is -H or -C 1-4 alkyl; and all other variables are as originally defined above; or a pharmaceutically acceptable salt thereof.
  • R 3 is -H or methyl. In another aspect of this embodiment, R 3 is -H.
  • R 4 is -CH 2 -phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, -OH, -C 1-4 alkyl, -C 1-4 fluoroallcyl, -O-C 1-4 alkyl, -O-C 1-4 fluoroalkyl, -(CH 2 ) 1-2 -N(R a R b ), -SO 2 R a , -(CH 2 ) 0-2 -CO 2 R a , -(CH 2 ) 0-2 -N(R a )CO 2 R b , -NO 2 , -SR a , -N(R a R b ) or phenyl; each R a and R b is independently is H or -C 1-4 alkyl; and all other variables are as originally defined above;
  • R 4 is -CH 2 -phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents, each of which is independently -F, -Br, -Cl, -OH, -C 1-4 alkyl, -C 1-4 fluoroalkyl, -O-C 1-4 alkyl, -SO 2- C 1-4 alkyl, -S-C 1-4 alkyl, -N(CH 3 ) 2 or -O-C 1-4 fluoroalkyl.
  • R 4 is p -fluorobenzyl or 2,3-dimethoxybenzyl.
  • the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, -OH, -C 1-4 alkyl, -C 1-4 fluoroalkyl, -O-C 1-4 alkyl, -O-C 1-4 fluoroalkyl, -(CH 2 ) 1-2 -N(R a R b ), -SO 2 R a , -(CH 2 ) 0-2 -CO 2 R a , -(CH 2 ) 0-2 -N(R a )CO 2 R b , -NO 2 , or phenyl.
  • the phenyl is optionally substituted with from 1 to 3 substituents, each of which is independently -F, -Br, -Cl, -OH, -C 1-4 alkyl, -C 1-4 fluoroalkyl, -O-C 1-4 alkyl, or -O-C 1-4 fluoroalkyl.
  • R 4 is p -fluorobenzyl or 2,3-dimethoxybenzyl.
  • a class of compounds of the present invention includes any compound of Formula (I), wherein
  • a sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (I), wherein
  • Another sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (I), wherein R 4 is 4-fluorobenzyl or 2,3-dimethoxybenzyl; and all other variables are as defined in the class; or a pharmaceutically acceptable salt thereof.
  • Still another sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (I), wherein R 2 is methyl; R 3 is -H; R 4 is 4-fluorobenzyl or 2,3-dimethoxybenzyl; each R a and R b is independently is H or -C 1-4 alkyl; and all other variables are as defined in the class; or a pharmaceutically acceptable salt thereof.
  • Another class of the present invention includes any compound of Formula (II): wherein
  • R 4 is -CH 2 -phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, -OH, -C 1-4 alkyl, -C 1-4 fluoroalkyl, -O-C 1-4 alkyl, -O-C 1-4 fluoroalkyl, -(CH 2 ) 1-2 -N(R a R b ), -SO 2 R a , -(CH 2 ) 0-2 -CO 2 R a , -(CH 2 ) 0-2 -N(R a )CO 2 R b , -NO 2 , or phenyl
  • a sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (II) exactly as defined in the preceding class, except that when R 2 is -C 1-4 alkyl substituted with -N(R a R b ), it is with the proviso that -N(R a R b ) is not attached to the carbon atom in the -C 1-4 alkyl group that is attached to the ring nitrogen (i.e., that the -N(R a R b ) group is not attached to the carbon atom alpha to the ring nitrogen).
  • Another sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (II), wherein
  • R 4 is -CH 2 -phenyl, wherein the phenyl is optionally substituted with 1 or 2 substituents each of which is independently -F, -Cl, -Br, -C 1-4 alkyl, -CF 3 , -O-C 1-4 alkyl, or -OCF 3 .
  • Another class of compounds of the present invention includes any compound of Formula (I), wherein
  • a sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (I), wherein
  • R 4 is -CH 2 -phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, -OH, -C 1-4 alkyl, -C 1-4 fluoroalkyl, -O-C 1-4 alkyl, -O-C 1-4 fluoroalkyl, -(CH 2 ) 1-2 -N(R a R b ), -SO 2 R a , -(CH 2 ) 0-2 -CO 2 R a , -(CH 2 ) 0-2 -N(R a )CO 2 R b , -NO 2 , or phenyl.
  • Another class of the present invention includes any compound of Formula (III): wherein R 2 is:
  • a sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (III) exactly as defined in the preceding class, except that when R 2 is -C 1-6 alkyl substituted with -N(R a R b ), it is with the proviso that -N(R a R b ) is not attached to the carbon atom in the -C 1-6 alkyl group that is attached to the ring nitrogen (i.e., that the -N(R a R b ) group is not attached to the carbon atom alpha to the ring nitrogen).
  • Another sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (III), wherein
  • R 4 is -CH 2 -phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, -OH, -C 1-4 alkyl, -C 1-4 fluoroalkyl, -O-C 1-4 alkyl, -O-C 1-4 fluoroalkyl, -(CH 2 ) 1-2 -N(R a R b ), -SO 2 R a , -(CH 2 ) 0-2 -CO 2 R a , -(CH 2 ) 0-2 -N(R a )CO 2 R b , -NO 2 , or phenyl.
  • R 4 is -CH 2 -phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, -OH, -C 1-4 alkyl, -C 1-4 fluoroalkyl, -O-C 1-4 alkyl, -O-C 1-4 fluoroalkyl, -(CH 2 ) 1-2 -N(R a R b ), -SO 2 R a , -(CH 2 ) 0-2 -CO 2 R a , -(CH 2 ) 0-2 -N(R a )CO 2 R b , -NO 2 , or phenyl.
  • additional embodiments of the present invention include, but are not limited to, compounds of Formula I wherein each of two or three or more of R 1 , R 2 , R 3 , R 4 , R a , R b , R c , R d , R k and R m is independently defined in accordance with its definition in one of the embodiments or an aspect thereof as set forth above, or in accordance with its definition in one of the foregoing classes set forth above or a sub-class or feature thereof. Any and all possible combinations of these variables in Formula I are additional embodiments within the scope of the present invention.
  • An aspect of the present invention is a compound selected from the group consisting of N-(2-ethoxybenzyl)-5-hydroxy-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide; N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide; N-(2,3-dimethoxybenzyl)-2- ⁇ 4-[(dimethylamino)methyl]phenyl ⁇ -5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide; N-(4-fluorobenzyl)-2- ⁇ 4-[(dimethylamino)methyl]phenyl ⁇ -5-hydroxy-1-methyl-6-oxo-1,6-dihydropyimidine-4-carboxamide; N-(2,3-dimethoxybenzyl
  • Another aspect of the present invention is a compound selected from the group consisting of:
  • the compounds of the present invention can be used in the following methods :
  • the present invention also includes a compound of the present invention (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation of a medicament for: (a) inhibiting HIV protease, (b) preventing or treating infection by HIV, or (c) preventing, treating or delaying the onset of AIDS.
  • the compounds of the present invention can optionally be employed in combination with one or more HIV/AIDS treatment agents selected from HIV/AIDS antiviral agents, anti-infective agents, and immunomodulators.
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(n) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt.
  • C 1-6 alkyl (or “C 1 -C 6 alkyl”) means linear or branched chain alkyl groups having from 1 to 6 carbon atoms and includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • C 1-4 alkyl means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • C 0 as employed in expressions such as "C 0-6 alkyl” means a direct covalent bond.
  • R 1 in Compound I is -C 0-6 alkyl-O-C 0-6 alkyl-R k
  • R 1 is -O-R k when both alkyl groups are C 0 alkyl.
  • an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond
  • the compound of Formula (II) has as a substituent at the 2-position of the pyrimidinone ring, wherein s is an integer equal to zero, 1 or 2. When s is zero, the substituent has the following structure:
  • -C 1-6 alkyl- refers to a C 1 to C 6 linear or branched alkyl group as just defined which is bivalent. It can alternatively be referred to as "C 1-6 alkylene” or "C 1-6 alkanediyl".
  • a class of alkylenes of particular interest with respect to the invention is -(CH 2 ) 1-6 -, and sub-classes of particular interest include -(CH 2 ) 1- 4-, -(CH 2 ) 1-3 -, -(CH 2 ) 1-2 -, and -CH2-.
  • C 2-5 alkynyl (or “C 2 -C 5 alkynyl”) means linear or branched chain alkynyl groups having from 2 to 5 carbon atoms and includes all of the pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, 2-propynyl, and ethynyl (or acetylenyl). Similar terms such as “C 2-3 alkynyl” have an analogous meaning.
  • C 3-8 cycloalkyl (or “C 3 -C 8 cycloalkyl”) means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).
  • C 3-7 cycloalkyl "C 3-6 cycloalkyl”
  • C 5-7 cycloalkyl and the like have analogous meanings.
  • C 3-7 azacycloalkyl (or “C 3 -C 7 azacycloalkyl”) means a saturated cyclic ring consisting of one nitrogen and from three to seven carbon atoms (i.e., azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl).
  • halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
  • C 1-6 haloalkyl (which may alternatively be referred to as “C 1 -C 6 haloalkyl” or “halogenated C 1 -C 6 alkyl”) means a C 1 to C 6 linear or branched alkyl group as defined above with one or more halogen substituents.
  • C 1-4 haloalkyl has an analogous meaning.
  • C 1-6 fluoroalkyl has an analogous meaning except that the halogen substituents are restricted to fluoro.
  • Suitable fluoroalkyls include the series (CH 2 ) 0-4 CF 3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.).
  • carbocycle refers to (i) a C 3 to C 8 monocyclic, saturated or unsaturated ring, (ii) a C 7 to C 12 bicyclic ring system, or (iii) a C 11 to C 16 tricyclic ring system, wherein each ring in (ii) or (iii) is independent of or fused to the other ring or rings and each ring is saturated or unsaturated.
  • the carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound.
  • fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term "fused bicyclic carbocycle” generally refers to a C 7 to C 10 bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system. Fused tricyclic carbocycles have an analogous meaning.
  • a subset of the fused bicyclic carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples of this subset include the following:
  • aryl refers to aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond.
  • Suitable aryl groups include phenyl, naphthyl, and biphenylenyl.
  • heterocycle broadly refers to (i) a 4- to 8-membered, saturated or unsaturated monocyclic ring, (ii) a 7- to 12-membered bicyclic ring system, or (iii) an 11 to 16-membered tricyclic ring system; wherein each ring in (ii) or (iii) is independent of or fused to the other ring or rings and each ring is saturated or unsaturated, and the monocyclic ring, bicyclic ring system, or tricyclic ring system contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) selected from N, O and S and a balance of carbon atoms (the monocylic ring typically contains at least one carbon atom and the ring systems typically contain at least two carbon atoms); and wherein any one or more of the nitrogen and sulfur heteroatoms is optional
  • the heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure.
  • the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
  • saturated heterocyclics form a subset of the heterocycles; i.e., the term “saturated heterocyclic” generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated.
  • saturated heterocyclic ring refers to a 4- to 8-membered saturated monocyclic ring which consists of carbon atoms and one or more heteroatoms selected from N, O and S.
  • Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).
  • Heteroaromatics form another subset of the heterocycles; i.e., the term “heteroaromatic” (alternatively “heteroaryl”) generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system.
  • heteroaryl generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system.
  • heteroaryl refers a 5- or 6-membered monocyclic aromatic ring which consists of carbon atoms and one or more heteroatoms selected from N, O and S.
  • heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl (i.e., ), imidazo(2,1-b)(1,3)thiazole, (i.e., ), and benzo-1,3-dioxolyl (i.e., ).
  • phenyl having as a substituent methylenedioxy attached to two adjacent carbon atoms.
  • tricyclic heterocycles include phenothiazinyl, carbazolyl, beta-carbolinyl, tetrahydro-beta-carbolinyl, acridinyl, phenazinyl, and phenoxazinyl.
  • an “unsaturated” ring is a partially or fully unsaturated ring.
  • an “unsaturated monocyclic C 6 carbocycle” refers to cyclohexene, cyclohexadiene, and benzene.
  • heterocycle described as containing from “1 to 4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4 heteroatoms.
  • any variable e.g., R a , R b , R c , R k , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituted e.g., as in "aryl which is optionally substituted with one or more substituents "
  • substituents include mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed.
  • the compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
  • N-substituted hydroxypyrimidinone compounds of the present invention may also occur as tautomers thereof. It is understood that the present invention includes all tautomers of the hydroxypyrimidinone compounds of Formula I, both singly and in mixtures.
  • the compounds of the present invention are useful in the inhibition of HIV integrase, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the prevention, treatment or the delay in the onset of consequent pathological conditions such as AIDS.
  • HIV human immunodeficiency virus
  • Preventing AIDS, treating AIDS, delaying the onset of AIDS, or preventing or treating infection by HIV is defined as including, but not limited to, treatment of a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
  • the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • the compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds.
  • the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
  • the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition.
  • the compounds of this invention are commercial products to be sold for these purposes.
  • Certain compounds representative of the present invention have also been tested in an assay for inhibition of acute HIV infection of T-lymphoid cells, conducted in accordance with Vacca, J.P. et al., Proc. Natl. Acad Sci. USA 1994, 91: 4096. These compounds demonstrated IC 95 's of about 20 micromolar or less.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof).
  • Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid
  • suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands such as quaternary ammonium salts.
  • pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
  • the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in the form of a unit dosage of a pharmaceutical composition containing a therapeutically effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
  • administration and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention mean providing the compound or a prodrug of the compound to the individual in need of treatment.
  • a compound of the invention or a prodrug thereof is provided in combination with one or more other active agents (e.g., antiviral agents useful for treating HIV infection or AIDS)
  • “administration” and its variants are each understood to include concurrent and sequential provision of the compound or prodrug and other agents.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combining the specified ingredients in the specified amounts.
  • pharmaceutically acceptable is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • active compound i.e., active ingredient
  • references to the amount of active ingredient are to the free acid or free base form of the compound.
  • compositions may be in the form of orally-administrable suspensions or tablets or capsules; nasal sprays, sterile injectible preparations, for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.
  • sterile injectible preparations for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.
  • These compositions can be prepared by methods and contain excipients which are well known in the art. Suitable methods and ingredients are described in Remington's Pharmaceutical Sciences , 18 th edition, edited by A. R. Gennaro, Mack Publishing Co., 1990.
  • the compounds of this invention can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses.
  • mammal e.g., human
  • One preferred dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses.
  • Another preferred dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses.
  • the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • the present invention is also directed to use of the HIV integrase inhibitor compounds of the present invention with one or more agents useful in the treatment of HIV infection or AIDS.
  • the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of one or more of the HIV/AIDS antivirals, imunomodulators, antiinfectives, or vaccines useful for treating HIV infection or AIDS.
  • Suitable antiviral agents include those listed in the following Table: ANTIVIRALS Drug Name Manufacturer (Tradename and/or Location) Indication (Activity) abacavir GW 1592 1592U89 Glaxo Welcome (ZIAGEN®) HIV infection, AIDS, ARC (nRTI) abacavir + lamivudine + zidovudine GlaxoSmithKline (TRIZIVIR®) HIV infection, AIDS, ARC (nnRTI) acemannan Carrington Labs (Irving, TX) ARC ACH 126443 Achillion Pharm.
  • ANTIVIRALS Drug Name Manufacturer Tradename and/or Location
  • Indication abacavir GW 1592 1592U89 Glaxo Welcome (ZIAGEN®) HIV infection, AIDS, ARC (nRTI) abacavir + lamivudine + zidovudine GlaxoSmithKline (TRIZIVIR®) HIV infection, AIDS, ARC (nnRTI) ace
  • HIV infections HIV infections, AIDS, ARC (nucleoside reverse transcriptase inhibitor) acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS, ARC adefovir dipivoxil GS 840 Gilead HIV infection, AIDS, ARC (RTI) AL-721 Ethigen (Los Angeles, CA) ARC, PGL, HIV positive, AIDS alpha interferon Glaxo Wellcome Kaposi's sarcoma, HIV, in combination w/Retrovir AMD3100 AnorMed HIV infection, AIDS, ARC (CXCR4 antagonist) amprenavir 141 W94 GW 141 VX478 (Vertex) Glaxo Wellcome (AGENERASE®) HIV infection, AIDS, ARC (PI) ansamycin LM 427 Adria Laboratories (Dublin, OH) Erb
  • AIDS, ARC HIV positive asymptomatic ddC (zalcitabine, dideoxycytidine) Hoffman-La Roche (HIVID®) HIV infection, AIDS, ARC (nRTI) ddI Dideoxyinosine Bristol-Myers Squibb (VIDEX®) HIV infection, AIDS, ARC; combination with AZT/d4T (nRTI) DPC 681 & DPC 684 DuPont HIV infection, AIDS, ARC (PI) DPC 961 & DPC 083 DuPont HIV infection AIDS, ARC (nnRTRI) emvirine Triangle Pharmaceuticals (COACTINON®) HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) EL10 Elan Corp, PLC (Gainesville, GA) HIV infection efavirenz (DMP 266) DuPont (SUSTIVA®) Merck (STOCRIN®) HIV infection, AIDS, ARC, HIV positive asymptomatic ddC (
  • HIV infection HIV infection, AIDS, ARC recombinant human interferon beta Triton Biosciences (Almeda, CA) AIDS, Kaposi's sarcoma, ARC interferon alfa-n3 Interferon Sciences ARC, AIDS indinavir Merck (CRIXIVAN®) HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC (PI) ISIS 2922 ISIS Pharmaceuticals CMV retinitis JE2147/AG1776 Agouron HIV infection, AIDS, ARC (PI) KNI-272 Nat'I Cancer Institute HIV-assoc, diseases lamivudine, 3TC Glaxo Wellcome (EPIVIR®) HIV infection, AIDS, ARC; also with AZT (nRTI) lobucavir Bristol-Myers Squibb CMV infection lopinavir (ABT-378) Abbott HIV infection, AIDS, ARC (PI) lopinavir
  • HIV inhibitor pentafusaide T-20 Trimeris HIV infection, AIDS, ARC (fusion inhibitor) peptide T octapeptide sequence Peninsula Labs (Belmont, CA) AIDS PRO 542 Progenics HIV infection, AIDS, ARC (attachment inhibitor) PRO 140 Progenics HIV infection, AIDS, ARC (CCR5 co-receptor inhibitor) trisodium phosphonoformate Astra Pharm. Products, Inc CMV retinitis, HIV infection, other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (PI) probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med.
  • a compound of the present invention can also be administered in combination with another HIV integrase inhibitor such as a compound described in WO 99/62513,WO 99/62520, or WO 99/62897.
  • a compound of the present invention can also be administered in combination with a CCR5 receptor antagonist, such as a compound described in WO 99/04794, WO 99/09984, WO 99138514, WO 00/59497, WO 00/59498, WO 00/59502, WO 00/59503, WO 00/76511, WO 00/76512, WO 00/76513.
  • WO 00/76514 , WO 00/76792, or WO 00/76793 are examples of the present invention.
  • the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of one or more HIV/AIDS antivirals, immunomodulators, antiinfectives, or vaccines useful for treating HIV infection or AIDS disclosed in the Table in WO 01/38332.
  • the compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials and reagents. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
  • the compounds of the present invention can be prepared by coupling suitable substituted alkyl 1-alkyl-1,6-dihydro-5-hydroxy-6-oxopyrimidine-4-carboxylates (or carboxylic acids or halides) with the appropriate amines, as represented by Scheme 1.
  • P is H or a protective group, typically an ester (e.g., benzoate or pivalate) that is normally removed under the conditions employed to convert the the methyl ester to the amide.
  • the ester protective group is typically used to purify the 2-substituted-5,6 dihydroxypyrimidine-4-carboxylates after their synthesis when the unprotected product cannot be crystallized from the reaction crude and/or for synthetic reasons.
  • Methyl 1-alkyl-1,6-dihydro-5-hydroxy-6-oxopyrimidine-4-carboxylates of formula 1-2 can be prepared as shown in Scheme 2, wherein amidoxime 2-1 can be reacted with DMAD in an appropriate solvent and at a suitable temperature to give the intermediate dihydroxypyrimidine 2-2 , followed by protection of the 5-hydroxy group in 2-2 with a suitable protecting agent such as benzoate or pivalate to give 2-3 , and then alkylation of nitrogen-1 to afford 1-2 .
  • a suitable protecting agent such as benzoate or pivalate
  • the alkyl group can be introduced on N 1 by reaction of 2-3 with an alkylating agent in the presence of an inorganic base (e.g., cesium carbonate). If a mixture of N- and O-alkylated derivatives results, the desired N-alkylated product 1-2 can be separated by flash chromatography.
  • Scheme 2 is exemplified in Example 1.
  • the unprotected compound can be isolated as such or it can be converted to 1-2 by reaction with a suitable protecting group.
  • Scheme 3 is exemplified in Example 2.
  • Amidoximes 2-1 and 3-1 are prepared from the corresponding nitriles by chemistry described herein (see Example 1, Step 1 and Example 2, Step 2).
  • Nitriles can be prepared from carboxylic acids by various procedures known in the art, including, for example, conversion to carboxamides by the procedure of of Pozdnev ( Tetrahedron Lett. 1989, 30 : 5193) (see also, Example 6, Step 2), and dehydration of the amide by the procedure of Waldmann ( Tetrahedron 1994, 50 : 11865) (see also, Example 6, Step 3).
  • haloderivative 3-1 or 3-4 can be synthesized by the bromination or chlorination of a suitable substrate affording a -CH 2 Br, -CH 2 Cl, -CHBr-, or -CHCl- group, followed by displacement of the halogen with a nucleophile ("Nu") such as an amine, thiol, or alcoholate to obtain the nucleophile-substituted methyl ester intermediate 3-2 or 3-5, which need not be isolated.
  • Nu nucleophile
  • Elaboration of the methyl ester functionality into the carboxamide will afford the final product 3-3 or 3-6.
  • Scheme 3 is exemplified in Example 5.
  • Scheme 4 depicts the preparation of compounds of the invention that contain an alkylated aliphatic amine in the substituent at the 2 position.
  • Nitrogen alkylation is achieved via a reductive amination or alkylation.
  • the nitrogen alkylation can be performed before formation of the amide ( via 4-3 ) or after formation of the amide ( via 4-2 ) depending on the substrate, with suitable deprotection as necessary.
  • Scheme 4 is exemplified in Examples 6 to 8 below.
  • the protecting groups can be removed at a convenient subsequent stage using methods known in the art. For example, in preparing the compounds of the invention it is sometimes necessary to protect one or more amino groups (e.g., amino groups present in substituents at the 2-position of the pyrimidinone ring) with, for example, a Boc or Cbz group or to protect hydroxy (e.g., the 5-hydroxy group on the pyrimidinone ring) with, for example, a benzoyl or benzyl group.
  • the Boc group can be removed by acid treatment (e.g., TFA) either before or after formation of the final amide at C-6 of the pyrimidinone nucleus.
  • the Cbz and benzyl groups are typically removed by catalytic hydrogenation or under strong acid conditions, either prior to or following formation of the final amide.
  • the benzoyl group can be removed concurrently with the formation of the final amide. Examples 6 and 12 below illustrate the use of a Boc protective group and of Boc, benzoyl and benzyl protective groups in the preparation of compounds of the invention.
  • Step 1 Tert-butyl-2-[amino(hydroxyimino)methyl]pyrrolidine-1-carboxylate
  • Step 2 Methyl 5-(benzoyloxy)-2-[1-( tert -butoxycarbonyl)pyrrolidin-2-yl]-6-hydroxypyrimidine-4-carboxylate
  • the reaction mixture was concentrated, and the resulting oil was diluted with ethyl acetate and washed with 1N HCl solution, saturated NaHCO 3 solution, saturated NaCl solution.
  • the crude oil obtained after organic solvent evaporation was purified by flash chromatography to obtain the title compound as a yellow solid.
  • Step 3 Methyl 5-(benzoyloxy)-2-[1-( tert -butoxycarbonyl)pyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Step 1 Benzyl 2-[[hydroxy(methyl)amino](imino)methyl]indoline-1-carboxylate
  • Step 2 Benzyl 2-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidi-2-yl]indoline-1-carboxylate
  • Step 1 The product of Step 1 was dissolved in CHCl 3 and dimethylacetylenedicarboxylate was added dropwise (1.2 eq.) at room temperature. After 4 h the mixture was evaporated, and the residue was dissolved in xylene and stirred at 160 °C for 2 days. The solvent was then evaporated, and the residue was dissolved in pyridine, after which (PhCO) 2 O (2 eq.) was added and the reaction mixture was stirred for 2 days. After evaporation, the resulting crude oil was diluted with EtOAc, washed with HCl 1N, dried over Na 2 SO 4 and evaporated. The product was purified by flash chromatography on silica gel (EtOAc/ petroleum ether, 1:4) to afford the title product.
  • Step 1 4,5-Dihydroxy-6-(methoxycarbonyl)pyrimidine-2-carboxylic acid
  • Step 3 Methyl 5-[(2,2-dimethylpropanoyl)oxyl-6-hydroxypyrimidine-4-carboxylate
  • Step 4 Methyl 5-[(2,2-dimethylpropanoyl)oxy]-1-mothyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Step 5 N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 1 Methyl 2-[4-(bromomethyl)phenyl]-5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Step 2 N-(4-Fluorobenzyl)-5-hydroxy-1-methyl-2-[4-(morpholin-4-ylmethyl)phenyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 1 4-( tert -Butoxycarbonyl)moipholine-3-carboxylic acid
  • Step 2 tert- Butyl 3-(aminocarbonyl)morpholine-4-carboxylate
  • Step 4 tert -Butyl 3-[(Z)-amino(hydroxyimino)methyl]morpholine-4-carboxylate
  • Step 5 Dimethyl-2-( ⁇ 2-amino-2-[4-(tert-butoxycarbonyl)morpholin-3-yl]ethenyl ⁇ oxy)but-2-enedioate
  • Step 6 tert -Butyl-3-[4,5-dihydroxy-6-(methoxycarbonyl)pyrimidin-2-yl]morpholine-4-carboxylate
  • Step 5 The adducts of Step 5 were refluxed in xylenes for 24 hours. Then the reaction was cooled down and concentrated in vacuo. Ethyl ether was added until precipitation of a solid that was filtered, washed with ethyl ether and dried to give the title pyrimidine as an orange solid.
  • Step 7 tert -Butyl-3-[5-(benzoyloxy)-4-hydroxy-6-(methoxycarbonyl)pyrimidin-2-yl]morpholine-4-carboxylate
  • Step 8 Alkylated derivatives 8A and 8B.
  • Step 9 tert-Butyl-3-(4- ⁇ [(4-fluorobenzyl)amino]carbonyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-morpholine-4-carboxylate
  • Step 10 N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-morpholin-3-yl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 11 N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • the compound from Step 10 was dissolved in MeOH and treated with triethylamine (1 eq.), sodium acetate (1.6 eq.), formaldehyde 37% w/w aq. soln. (3 eq.), and sodium cyanoborohydride (1.43 eq.). The mixture was left stirring at room temperature for 1 hour. The reaction mixture was concentrated and the title compound was obtained by RP-HPLC purification (C 18 , eluting with water and acetonitrile containing 0.1 % TFA), as its trifluoroacetate salt.
  • N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide has been resolved into its enantiomers by semi preparative chiral HPLC using the following conditions:
  • Step 1 Methyl 1-methyl-2-(4-tert-butoxycarbonylpiperazin-2-yl))-5-benzoyloxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Methyl 1-methyl-2-(4- tert -butoxycarbonyl-1-benzyloxycarbonylpiperazin-2-yl))-5-benzoyloxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate prepared from 1-[(benzyloxy)carbonyl]-4-( tert -butoxycarbonyl)piperazine-2-carboxylic acid (Bigge et al, Tetrahedron Lett. 1989, 30 : 5193) by procedures similar to those set forth in Examples 2 or 3 in combination with a deprotection step) was dissolved in MeOH and hydrogenated at atm pressure on 10% Pd/C for 1 hour. The crude title product was obtained after filtration and evaporation.
  • Step 2 N-(4-fluorobenzyl) 1-methyl-2-(4- tert -butoxycarbonylpiperazin-2-yl))-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 3 N-(4-fluorobenzyl) 1-methyl-2-(4- tert -butoxycarbonyl-1-methylpiperazin-2-yl))-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 4 N -(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methylpiperazin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 5 2-(4-ethyl-1-methylpiperazin-2-yl)- N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Triethylamine (2 eq.), NaCNBH 3 (1.4 eq.), AcONa (1.6 eq.) and CH 3 CHO (1 eq.) were added to a methanolic solution of the crude product obtained in step 4.
  • the reaction was stirred at room temperature for 1 hour.
  • the title product was obtained as its trifluroacetate salt by preparative RP-HPLC purification (C18, gradient of CH 3 CN/H 2 O + 0.01 %TFA).
  • Step 1 N -(4-fluorobenzyl)-5-hydroxy-2-[4-(isopropylsulfonyl)-1-methylpiperazin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Methyl 5-(benzoyloxy)-1-methyl-6-oxo-2-piperidin-2-yl-1,6-dihydropyrimidine-4-carboxylate (prepared from 1-(benzyloxycarbonyl)piperidine-2-carboxylic acid by procedures similar to those set forth in Examples 1 or 2 in combination with a deprotection step) was suspended in THF and treated with 3 eq. of triethylamine and 3 eq. of methyl iodide at 40 °C. After stirring for 5 h, THF was evaporated and residue poured into EtOAc and washed with brine. Organic phase was dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure.
  • Step 1 Methyl 5-(benzoyloxy)-1-methyl-6-oxo-2-pyrrolidin-2-yl-1,6-dihydropyrimidine-4-carboxylate
  • Step 2 2-(1-Acetylpyrrolidin-2-yl)- N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 1 Methyl 2-(2,3-dihydro-1 H -indol-2-yl)-1-methyl-5-benzoyloxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Step 2 Methyl 2-(1-benzoyl-2,3-dihydro-1 H -indol-2-yl)-5-benzoyloxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Step 3 2-(1-benzoyl-2,3-dihydro-1 H -indol-2-yl)- N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 2 The crude product of Step 2 was dissolved in MeOH and 4-fluorobenzylamine (3.5 eq.) added. The solution was stirred at 60 °C over night. The title product was obtained by preparative RP-HPLC (C18, gradient of CH 3 CN/H 2 O + 0.01 %TFA).
  • Step 1 Methyl 2-(1,2,3,4-tetrahydroquinolin-2-yl)-1-methyl-5-benzoyloxy-6-oxo-1,6-dihydropyrimidme-4-carboxylate
  • Step 2 Methyl 5-benzoyloxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-2-yl]-1,6-dihydropyrimidine-4-carboxylate
  • Step 1 The residue of Step 1 was dissolved in dichloromethane. Pyridine, picolinoyl chloride hydrochloride and a catalytic amount of DMAP were added. A further addition of the reactants was made after two hours. After evaporation of the solvent, the residue was diluted with EtOAc, the organic phase washed with water, dried (Na 2 SO 4 ) and evaporated to afford the title product.
  • Step 3 N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-2-yl]-1,6-dihydropyrirnidine-4-carboxamide
  • Step 2 The residue of Step 2 was dissolved in DMF and 4-fluorobenzylamine (3 eq.) was added. The reaction mixture was stirred at 90°C for 1 h. The title compound was purified by preparative HPLC and isolated as its trifluoroacetic salt (C18, gradient of CH 3 CN/H 2 O + 0.01% TFA).
  • Step 1 Methyl 2-[(2S,4 R )-1-benzoyl-4-(benzyloxy)pyrrolidin-2-yl]-5-(benzoyloxy)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Step 2 2-[(2 S ,4 R )-1-benzoyl-4-(benzyloxy)pyrrolidin-2-yl]- N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 1 The compound of Step 1 was dissolved in methanol and 4-fluorobenzylamine (5 eq.) was added. The mixture was refluxed overnight. After cooling, the reaction mixture was filtered and washed with ethyl ether to obtain the title product as a white solid.
  • Step 3 2-[(2 S ,4 R )-1-benzoyl-4-hydroxypyrrolidin-2-yl]-N (4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo- 1,6-dihydropyrimidine-4-carboxamide
  • Step 2 The title compound of Step 2 was dissolved in AcOH and 10% Pd/C (10% weight) was added. The mixture was stirred under H 2 at atmosphere overnight. Pd/C was filtered, AcOH evaporated in vacuo, and the resulting title compound was washed with methanol.
  • Step 1 2-(2,2-dimethoxyethyl)- N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Methyl 2-(2,2-dimethoxyethyl)-5-benzoyloxy-l-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.0 eq.) (prepared from 3,3-dimethoxypropionitrile by procedure similar to those set forth in Examples 1 or 2) in dry MeOH was treated with 4-fluorobenzyl amine (2.5 eq.) at reflux for 2 hours. Solvent was removed in vacuo and residue triturated with Et 2 O to obtain the title product.
  • Step 2 N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-(2-oxoethyl)-1,6-dihydropyrimidine-4-carboxamide
  • Step 1 The product of Step 1 was treated with a mixture HCl 1N/THF for 1 hour at 40 °C. Organics were removed in vacuo and residue extracted in DCM, dried over Na 2 SO 4 and concentrated to give the title compound as a foam which was immediately reacted in the following reductive amination. MS: mlz 320 (M + H)+.
  • Step 3 2-[2-(4-benzoylpiperazin-1-yl)ethyl]- N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 2 The product of Step 2 was dissolved in MeOH and treated with sodium acetate (1.6 eq.), 1-benzoylpiperazine (2 eq.), and sodium cyanoborohydride (1.43 eq.). The mixture was left stirring at room temperature for 1hour. The reaction mixture was concentrated and the title compound was obtained by RP-HPLC purification (C 18 , eluting with water and acetonitrile containing 0.1 % TFA).
  • Step 1 Methyl 1-allyl-5-[(2,2-dimethylpropanoyl)oxy]-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Step 2 N -(4-fluorobenzyl)-5-hydroxy-1-(2-hydroxy-3-morpholin-4-ylpropyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 3 Benzyl-(2S,4S)-2-aminocarbonyl-4-fluoropyrrolidine-1-carboxylate
  • Step 4 Benzyl-(2S,4S)-2-cyano-4-fluoropyrrolidine-1-carboxylate
  • Step 5 Benzyl-(2S,4S)-2-[amino(hydroxyimino)methyl]-4-fluoropyrrolidine-1-carboxylate
  • Step 6 Dimethyl-2- ⁇ [(amino- ⁇ (2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl ⁇ methylidene)amino]oxy ⁇ but-2-enedioate
  • Step 7 Methyl-2- ⁇ (2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl ⁇ -5,6-dihydroxypyrimidine-4-carboxylate
  • Step 8 Methyl-5-(benzoyloxy)-2-1(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl ⁇ -6-hydroxypyrimidine-4-carboxylate
  • Step 9 Methyl-5-(benzoyloxy)-2- ⁇ (2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl ⁇ -1-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxylate.
  • reaction mixture was then cooled down and glacial acetic acid (0.2 eq.) was added, followed by water and ethyl acetate.
  • the aqueous layer was separated and extracted with ethyl acetate; the organic phase was dried over Na 2 SO 4 and filtered to give, after concentration, a crude that was purified by flash chromatography (eluent petroleum ether: ethyl acetate from 4:6 to 2:8) to give the title compound as a 4.6:5.4 mixture of rotamers by NMR.
  • Step 10 Methyl-2-[(2S,4S)-1-acetyl-4-fluoropyrrolidin-2-yl]-5-(benzoyloxy)-6-hydroxypyrimidine-4-carboxylate.
  • Step 11 2-[(2S,4S)-1-acetyl-4.-fluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide.
  • Methyl-2-[(2S,4S)-1-acetyl-4-fluoropyrrolidin-2-yl]-5-(benzoyloxy)-6-hydroxypyrimidine-4-carboxylate was dissolved in MeOH (0.12 N) and treated with 4-F-benzylamine (3 eq.) in a sealed tube. The reaction mixture was stirred at 65°C for 18 hours, then it was cooled down. The solvent was evaporated and the residue was washed with ethyl ether several times to obtain a solid that was recrystallized from ethanol and washed again with ethyl ether to give the title compound as a 7.3:2.7 mixture af rotamers by NMR.
  • Step 1 (4 R )-1-[(Benzyloxy)carbonyl]-4-methoxy-L-proline
  • Step 2 Benzyl-(2 S ,4 R )-2-cyano-4-methoxypyrrolidine-1-carboxylate
  • Step 3 Benzyl-(2 S ,4 R )-2-[amino(hydroxyimino)methyl]-4methoxypyrrolidine -1-carboxylate
  • Step 4 Dimethyl-2- ⁇ [(amino- ⁇ (2 S ,4 R )-1-[(benzyloxy)carbonyl]-4-methoxypyrrolidin-2-yl ⁇ methylidene)amino]oxy ⁇ but-2-enedioate
  • Step 5 Methyl 5-(benzoyloxy)-2- ⁇ (2S,4R ⁇ -1-[(benzyloxy)carbonyl]-4-methoxypyrrolidin-2-yl ⁇ -6-hydroxypyrimidine-4-carboxylate
  • Step 6 Methyl-5-(benzoyloxy)-2- ⁇ (2 S ,4 R )-1-[(benzyloxy)carbonyl]-4-methoxypyrrolidin-2-yl ⁇ -1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Step 7 Benzyl-(2 S ,4 R )-2-(4- ⁇ [ ⁇ 4-fluorobenzyl)amino]carbonyl ⁇ -5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methoxypyrrolidine-1-carboxylate
  • Step 8 N - (4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-methoxypyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Benzyl-(2 S ,4 R )-2-(4- ⁇ [(4-fluorobenzyl)amino]carbonyl ⁇ -5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methoxypyrrolidine-1-carboxylate was dissolved in methanol and Pd/C 10%wt (14%w/w) was added. The mixture was stirred under H 2 atmosphere at room temperature. After 2 hours the reaction mixture was filtered and methanol was removed in vacuo to give title compound.
  • Step 9 2- ⁇ (2 S ,4 R )-1-[(dimethylamino)(oxo)acetyl]-4-methoxypyrrolidin-2-yl ⁇ - N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 3 Benzyl 2-amino-2-(hydroxyimino)-1,1-dimethylethylcarbamate.
  • Step 4 Methyl 2-(1- ⁇ [(benzyloxy)carbonyl]amino ⁇ -1-methylethyl)-5,6-dihydroxypyrimidine-4-carboxylate.
  • Benzyl 2-amino-2-(hydroxyimino)-1,1-dimethylethylcarbamate was suspended in chloroform and treated with 1.2 eq of dimethylacetylenedicarboxylate and reaction was refluxed overnight. After cooling at room temperature, volatiles were evaporated and the residue was taken into xylene and heated at 145 °C for 48 h. The reaction mixture was stirred at room temperature overnight to allow the precipitation of the product (5) as a light brown solid. This solid was collected by filtration and washed with diethyl ether.
  • Step 5 Methyl 5-(benzoyloxy)-2-(1- ⁇ [(benzyloxy)carbonyl]amino ⁇ -1-methylethyl)-6-hydroxypyrimidine-4-carboxylate.
  • Step 6 Methyl 5-(benzoyloxy)-2-(1- ⁇ [(benzyloxy)carbonyl]amino ⁇ -1-methylethyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Step 8 Benzyl 1-(4- ⁇ [(4-fluorobenzyl)amino]carbonyl ⁇ -5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-l-methylethylcarbamate.
  • Step 9 2-(1-amino-1-methylethyl)- N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide.
  • Step 10 Methyl ⁇ [1-(4- ⁇ [(4-fluorobenzyl)amino]carbonyl ⁇ -5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]amino ⁇ (oxo)acetate.
  • Step 11 N 1 -[1-(4- ⁇ [(4-fluorobenzyl)amino]carbonyl ⁇ -5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]- N 2 , N 2 - dimethylethanediamide (11).
  • Step1 N -(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1- ⁇ [(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino ⁇ ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Triethyl amine (3 eq) was added to the mixture and the reaction was stirred overnight at room temperature.
  • Title product was isolated by prep RP HPLC (C18, acetonitrile/water containing 0.1% of trifluoroacetic acid as eluant).
  • Step 2 1-Benzyl 2-methyl (2 S )-4,4-difluoropyrrolidine-1,2-dicarboxylate
  • Step 4 Benzyl-(2S)-2-aminocarbonyl-4,4-difluoropyrrolidine-1-carboxylate
  • Step 5 Benzyl-(2 S )-2-cyano-4,4-difluoropyrrolidine-1-carboxylate
  • Step 6 Benzyl-(2 S )-2-[amino(hydroxyimino)methyl]-4,4-difluoropyrrolidine-1-carboxylate
  • Step 7 Dimethyl-2- ⁇ [(amino- ⁇ (2 S )-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl ⁇ methylidene)amino]oxy ⁇ but-2-enedioate
  • Step 8 Methyl-2- ⁇ (2S)-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl)-5,6-dihydroxypyrimidine-4-carboxylate
  • Step 9 Methyl 5-(benzoyloxy)-2- ⁇ (2 S )-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl ⁇ -6-hydroxypyrimidine-4-carboxylate
  • Step 10 Methyl-5-(benzoyloxy)-2- ⁇ (2S)-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl ⁇ -1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Step 11 Benzyl-(2 S )-4,4-difluoro-2-(4- ⁇ [(4-fluorobenzyl)amino]carbonyl ⁇ -5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)pyrrolidine-1-carboxylate
  • Step 12 (2 S )-4,4-difluoro-2-(4- ⁇ [(4-fluorobenzyl)amino]carbonyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)pyrrolidinium trifluoroacetate
  • Step 13 2- ⁇ (2 S )-1-[(dimethylamino)(oxo)acetyl]-4,4-difluoropyrrolidin-2-yl ⁇ - N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  • Step 2 1-benzyl 4- tert -butyl 2-[(Z)-amino( ⁇ [(1 E )-3-methoxy-1-(methoxycarbonyl)-3-oxoprop-1-enyl]oxy ⁇ imino)methyl]-2-methyl piperazine-1,4-dicarboxylate.
  • Step3 1-benzyl 4- tert -butyl 2-[5-(benzoyloxy)-4-hydroxy-6-(methoxycarbonyl) pyrimidin-2-yl]-2-methylpiperazine-1,4-dicarboxylate
  • Step 4 1-benzyl 4- tert -butyl 2-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-2-methylpiperazine-1,4-dicarboxylate.
  • Step 5 Methyl 5-(benzoyloxy)-2-[4-( tert -butoxycarbonyl)-2-methylpiperazin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  • Step 6 2-[1,2-dimethyl-4-(methylsulfonyl)piperazin-2-yl]- N -(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide.
  • Tables 1 and 2 below list compounds of the present invention which have been prepared.
  • the tables provide the structure and name of each compound, the mass of its molecular ion plus 1 (M + ) or molecular ion minus 1 (M-) as determined via FIA-MS, and the synthetic scheme employed to prepare the compound.
  • M + molecular ion plus 1
  • M- molecular ion minus 1
  • the synthetic scheme identified as "1*" in Table 1 is identical to Scheme 1 above, except for an additional deprotection step to remove Boc, Cbz, or benzyl present in the 2-substituent in the pyrimidinone ring.

Claims (39)

  1. Composé de formule (I) :
    Figure imgb0171
    dans laquelle
    R1 représente
    (1) -H
    (2) -un groupe -(alkyle en C1-6), qui est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, -OH, -CN, -O(alkyle en C1-6), -O(halogénoalkyle en C1-6), -C(=O)Ra, -CO2Ra, -SRa, -S(=O)Ra, -N(RaRb), -C(=O)-(alkyle en C0-6)-N(RaRb), N (Ra) -C (=O) - (alkyle C0-6) -N (RbRc), -SO2Ra, -N (Ra) SO2Rb, - SO2N(RaRb),
    Figure imgb0172
     -N (Ra) -C (=O) Rb, ou -N(Ra)C(=O)C(=O)N(RaRb),
    (3) -Rk
    (4) un groupe - (alkyle en C1-6) -Rk, dans lequel :
    (i) le groupe alkyle est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, -OH, -CN, -O(alkyle en C1-6), -O-(halogénoalkyle en C1-6) -N(RaRb), -N(Ra)CO2Rb, -N(Ra)C(=O) (alkyle en C0-6)-N(RbRc), ou -N(Ra)-(alkyle en C2-6) -OH, sous réserve que le groupe -OH ne soit pas attaché par l'atome de carbone alpha à N(Ra) ; et
    (ii) le groupe alkyle est éventuellement monosubstitué par un groupe -Rs,-(alkyle en C1-6)-Rs, N (Ra) -C (=O) - (alkyle en C0-6) -Rs, -N (Ra) - (alkyle en C0-6) -Rs, O- (alkyle en C0-6)-Rs, ou -N (Ra) -C (=O) - (alkyle en C0-6) -Rs ; où Rs représente
    (a) un groupe aryle qui est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, -OH, - (alkyle en C1-6),
    - (alkyle en C1-6) -ORa, - (halogénoalkyle en C1-6), -O-(alkyle en C1-6),
    -O-(halogénoalkyle en C1-6), méthylènedioxy attaché à deux atomes de carbone adjacents, ou aryle ;
    (b) un cycle hétérocyclique saturé à 4 à 8 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; dans lequel le cycle hétérocyclique saturé est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, un groupe - (alkyle en C1-6),
    - (alkyle en C1-6) -ORa, - (halogénoalkyle en C1-6), -O- (alkyle en C1-6),
    -O- (halogénoalkyle en C1-6), -C (=O) Ra, -CO2Ra,
    C(=O)-(alkyle en C0-6) -N (RaRb), -SO2Ra, oxo, aryle ou (alkyle en C1-6) -aryle ; ou
    (c) un cycle hétéroaromatique à 5 à 7 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; lequel cycle hétéroaromatique saturé est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, un groupe
    - (alkyle en C1-6), -(alkyle en C1-6)-ORa, -(halogénoalkyle en C1-6), -O- (alkyle en C1-6), -O- (halogénoalkyle en C1-6), oxo, ou aryle ;
    (5) un groupe - (alkyle en C0-6) -O- (alkyle en C0-6)-Rk,
    (6) un groupe - (alkyle en C0-6) -S (O) n- (alkyle en C0-6) -Rk,
    (7) un groupe -(alkyle en C1-6)-ORk,
    (8) un groupe -O- (alkyle en C1-6)-O- (alkyle en C1-6)-Rk
    (9) un groupe -O- (alkyle en C1-6) -S (O) nRk,
    (10) un groupe - (alkyle en C0-6)-N(Ra) -Rk,
    (11) un groupe - (alkyle en C0-6)-N(Ra)- (alkyle en C1-6) -Rk,
    (12) un groupe - (alkyle en C0-6)-N(Ra)-(alkyle en C1-6)-ORk,
    (13) un groupe - (alkyle en C0-6)-C(=O)-Rk,
    (14) un groupe - (alkyle en C0-6)-C(=O)N(Ra)-(alkyle en C0-6) - Rk,
    (15) un groupe - (alkyle en C0-6)-N(Ra)C(=O)-(alkyle en C0-6) - Rk,
    (16) un groupe -(alkyle en C0-6)-N(Ra)C(=O)-O-(alkyle en C0-6 )-Rk, ou
    (17) un groupe -(alkyle en C0-6)-N(Ra)C(=O)C(=O)Rk
    R2 représente un groupe -(alkyle en C1-6) qui est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment
    (1) un atome d'halogène
    (2) -OH,
    (3) -CN,
    (4) un groupe -O- (alkyle en C1-6),
    (5) un groupe -O-(halogénoalkyle en C1-6),
    (6) -C(=O)Ra,
    (7) -CO2Ra,
    (8) -SRa,
    (9) -S(=O)Ra,
    (10) -N(RaRb),
    (11) -C (=O) N (RaRb) ,
    (12) un groupe -N (Ra) -C (=O) - (alkyle en C1-6)-N(RbRc),
    (13) -SO2Ra,
    (14) -N (Ra) SO2Rb,
    (15) -SO2N (RaRb) ,
    (16) -N(Ra)-C(Rb)=O,
    (17) un groupe - (cyloalkyle en C3-8),
    (18) un groupe aryle, lequel groupe aryle est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, un groupe - (alkyle en C1-6), -(halogénoalkyle en C1-6),
    -O- (alkyle en C1-6), -O- (halogénoalkyle en C1-6), -(alkyle en C0-6)-N(RaRb), ou - (alkyle en C1-6) substitué par un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, 0 et S ;
    le cycle hétérocyclique saturé étant éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un groupe -(alkyle en C1-6), oxo, ou un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; ou
    (19) un hétérocycle monocyclique à 5 à 8 chaînons qui est saturé ou insaturé et contient de 1 à 4 hétéroatomes indépendamment choisis parmi N, 0 et S ; lequel hétérocycle est éventuellement substitué par un ou plusieurs substituants dont chacun représente indépendamment un groupe - (alkyle en C1-6), -O (alkyle en C1-6), oxo, phényle ou naphtyle ;
    sous réserve qu'aucun des substituants suivants ne soit attaché à l'atome de carbone dans le groupe
    -(alkyle en C1-6) qui est attaché au carbone d'azote du cycle : atome d'halogène, groupe -OH, -O- (alkyle en C1-6),
    -O- (halogénoalkyle en C1-6), -SRa, -S (=O) Ra, ou -N (Ra) - C (Rb) =O ;
    R3 représente -H ou un groupe - (alkyle en C1-6) ;
    R4 représente
    (1) H,
    (2) un groupe alkyle en C1-6 qui est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, -OH,
    -O- (alkyle en C1-6), -O-(halogénoalkyle en C1-6), -NO2, - N(RaRb), -C(=O)Ra, -CO2Ra, -SRa, -S(=O)Ra, -SO2Ra ou - N (Ra)CO2Rb,
    (3) un groupe alkyle en C1-6 qui est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, -OH, -O- (alkyle en C1-4) et qui est substitué par un ou deux substituants, chacun étant indépendamment :
    (i) un groupe cycloalkyle en C3-8,
    (ii) un groupe aryle,
    (iii) un carbocycle bicyclique condensé constitué d'un cycle benzène condensé avec un groupe cycloalkyle en C5-7,
    (iv) un cycle hétérocyclique saturé à 5 ou 6 chaînons, contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S,
    (v) un cycle hétéroaromatique à 5 ou 7 chaînons, contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S, ou
    (vi) un hétérocyclique bicyclique condensé à 9 ou 10 chaînons contenant de 1 à 4 atomes hétéroatomes indépendamment choisis parmi N, 0 et S, dans lequel au moins un des cycles est aromatique,
    (4) un groupe alkynyle en C2-5 éventuellement substitué par un groupe aryle,
    (5) un groupe cycloalkyle en C3-8 éventuellement substitué par un groupe aryle,
    (6) un groupe aryle,
    (7) un carbocycle bicyclique condensé constitué d'un cycle benzène condensé avec un groupe cycloalkyle en C5-7,
    (8) un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes choisis parmi N, O et S,
    (9) un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes choisis parmi N, O et S, ou
    (10) un hétérocyclique bicyclique condensé à 9 ou 10 chaînons contenant de 1 à 4 hétéroatomes choisis parmi N, O et S, dans lesquels au moins un des cycles est aromatique ;

    où
    chaque groupe aryle dans (3)(ii) ou le groupe aryle dans (4), (5) ou (6) ou chaque carbocyclique condensé dans (3)(iii) ou le carbocycle condensé dans (7) est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, -OH, un groupe
    - (alkyle en C1-6), - (alkyle en C1-6)-ORa, -(halogénoalkyle en C1-6),
    -O-(alkyle en C1-6), -O- (halogénoalkyle en C1-6), -CN, NO2, -N(RaRb), - (alkyle en C1-6) -N(RaRb), -C(=O)N(RaRb), -C(=O)Ra, -CO2Ra, -(alkyle en C1-6)-CO2Ra, -OCO2Ra, -SRa, -S(=O)Ra, -SO2Ra, -N(Ra)SO2Rb, -SO2N(RaRb), N(Ra) C (=O)Rb, -N(Ra)CO2Rb,- (alkyle en C1-6)-N (Ra)CO2Rb, aryle, - (alkyle en C1-6) -aryle, -O-aryle ou -(alkyle en C0-6)-het, où het représente un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, 0 et S, het est éventuellement condensé avec un cycle benzène, et éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un groupe - (alkyle en C1-6), (halogénoalkyle en C1-6), -O-(alkyle en C1-6),
    -O-(halogénoalkyle en C1-6), oxo, ou -CO2Ra ;
    chaque cycle hétérocyclique saturé dans (3) (iv) ou le cycle hétérocyclique saturé dans (8) est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, un groupe
    -(alkyle en C1-6), (halogénoalkyle en C1-6), -O- (alkyle en C1-6),
    -O-(halogénoalkyle en C1-6), oxo, aryle ou un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; et chaque cycle hétéroaromatique dans (3)(v) ou le cycle hétéroaromatique dans (9) ou chaque cycle bicyclique condensé dans (3)(vi) ou l'hétérocycle bicyclique condensé dans (10) est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, un groupe
    - (alkyle en C1-6), - (halogénoalkyle en C1-6),
    -O-(alkyle en C1-6), -O-(halogénoalkyle en C1-6), oxo, aryle
    ou
    - (alkyle en C1-6)-aryle ;
    ou bien R3 et R4 ensemble avec l'atome d'azote auquel ils sont tous deux attachés forment un groupe azacycloalkyle en C3-7 qui est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un groupe
    - (alkyle en C1-6) ou oxo ;
    chaque Ra, Rb, Rc et Rd représente indépendamment -H ou un groupe - (alkyle en C1-6) ;
    Rk représente un carbocycle ou un hétérocycle, le carbocycle ou l'hétérocycle étant éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment
    (1) un atome d'halogène
    (2) -OH
    (3) -CN,
    (4) un groupe -(alkyle en C1-6) qui est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, un groupe -OH, -CN, -O- (alkyle en C1-6), -O- (halogénoalkyle en C1-6), -C (=O) Ra, -CO2Ra, -SRa, -S(=O) Ra, -N (RaRb), -C (=O) - (CH2) 0-2N (RaRb), N(Ra)-C(=O)- (CH2) 0-2N (RbRc) -SO2Ra, -N(Ra) SO2Rb, -SO2N (RaRb), ou N (Ra) -C (Rb)=O,
    (5) un groupe -O-(alkyle en C1-6) qui est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, un groupe -OH, -CN, -O- (alkyle en C1-6), -O- (halogénoalkyle en C1-6), -C (=O) Ra, -CO2Ra , -SRa, -S (=O) Ra, -N (RaRb) , -C (=O) - (CH2) 0-2N (RaRb), N (Ra) -C (=O) - (CH2) 0-2N (RbRc) , -SO2Ra, -N (Ra) SO2Rb, -SO2N (RaRb), ou N(Ra)-C(Rb)=O,
    (6) -NO2
    (7) oxo,
    (8) -C(=O)Ra,
    (9) -CO2Ra,
    (10) -SRa,
    (11) -S(=O)Ra,
    (12) -N (RaRb) ,
    (13) -C(=O)N(RaRb),
    (14) -C(=O)-(alkyle en C1-6) -N (RaRb),
    (15) -N(Ra)C(=O)Rb
    (16) -SO2Ra,
    (17) -SO2N (RaRb),
    (18) -N(Ra)SO2Rb
    (19) -Rm
    (20) un groupe (alkyle en C1-6)-Rm, dans lequel le groupe alkyle est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, -OH, -CN, -(halogénoalkyle en C1-6), -O-(alkyle en C1-6), -O- (halogénoalkyle en C1-6) , -C (=O)Ra, -CO2Ra, -SRa, -S (=O) Ra, -N(RaRb) , -N (Ra) CO2Rb, -SO2Ra, -N (Ra) SO2Rb, -SO2N (RaRb), ou N (Ra) -C (Rb) =O,
    (21) un groupe -(alkyle en C0-6)-N(Ra)-(alkyle en C0-6)-Rm
    (22) un groupe -(alkyle en C0-6)-O-(alkyle en C0-6) -Rm
    (23) un groupe -(alkyle en C0-6)-S-(alkyle en C0-6) -Rm
    (24) un groupe -(alkyle en C0-6) -C (=O) - (alkyle en C0-6) -Rm
    (25) un groupe -C(=O) -O- (alkyle en C0-6) -Rm
    (26) un groupe -C(=O) N (Ra) - (alkyle en C0-6) -Rm
    (27) un groupe -N(Ra) C (=O) -Rm
    (28) un groupe -N(Ra) C (=O) - (alkyle en C1-6) -Rm' dans lequel le groupe alkyle est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, -OH, -CN, -(halogénoalkyle en C1-6), -O-(alkyle en C1-6), -O-(halogénoalkyle en C1-6), -C(=O)Ra, -CO2Ra, -SRa, -S(=O)Ra, -N(RaRb), -N(Ra)CO2Rb, -SO2Ra, -N(Ra)SO2Rb, -SO2N (RaRb), ou N (Ra) -C (Rb) =O,
    (29) un groupe -N(Ra)-C(=O)-N(Rb)-(alkyle en C0-6)-Rm
    (30) un groupe -N(Ra)-C (=O)-O-(alkyle en C1-6)-Rm
    (31) un groupe -N(Ra)-C (=O) -N (Rb) -SO2- (alkyle en C0-6) -Rm
    (32) un groupe -C(=O)-C(=O)-N(RaRb),
    (33) un groupe -C(=O)-(alkyle en C1-6)-SO2Ra, ou
    (34) un groupe -C(=O)-C(=O)Rm ;
    le carbocycle dans Rk est (i) un cycle monocyclique en C3- à C8, saturé ou insaturé, (ii) un système cyclique bicyclique en C7 à C12, ou (iii) un système cyclique tricyclique en C11 à C16, chaque cycle dans (ii) ou (iii) étant indépendant ou condensé avec les autres cycles, et chaque cycle étant saturé ou insaturé ;
    l'hétérocycle dans Rk est (i) un cycle monocyclique de 4 à 8 chaînons, saturé ou insaturé, (ii) un système cyclique bicyclique de 7 à 12 chaînons, ou (iii) un système cyclique tricyclique de 11 à 16 chaînons ; chaque cycle dans (ii) ou (iii) étant indépendant ou condensé avec l'autre ou les autres cycles, et chaque cycle étant saturé ou insaturé ; le cycle monocyclique, le système cyclique bicyclique ou le système cyclique tricyclique contenant de 1 à 6 hétéroatomes choisis parmi N, O et S et le complément en atomes de carbone ; et chacun du ou des hétéroatomes d'azote et de soufre étant éventuellement oxydé, et chacun du ou des hétéroatomes d'azote étant éventuellement quaternisé ;
    chaque Rm représente indépendamment un groupe cycloalkyle en 3-8 ; aryle ; un hétérocycle monocyclique de 5 à 8 chaînons qui est saturé ou insaturé et contient de 1 à 4 hétéroatomes indépendamment choisi parmi N, 0 et S ; ou un hétérocyclique bicyclique de 9 à 10 chaînons, qui est saturé ou insaturé et contient de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; où chacun du ou des hétéroatomes d'azote et de soufre dans l'hétérocycle ou l'hétérocycle bicyclique est éventuellement oxydé et chacun du ou des hétéroatomes d'azote est éventuellement quaternisé ;
    et où le groupe cycloalkyle ou le groupe aryle défini dans Rm est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, un groupe -(alkyle en C1-6) éventuellement substitué par un groupe -O-(alkyle en C1-4), - (halogénoalkyle en C1-6), O- (alkyle en C1-6),
    -O- (halogénoalkyle en C1-6), -N (RaRb), aryle ou
    - (alkyle en C1-6) -aryle ; et
    l'hétérocyclique monocyclique ou bicyclique défini dans Rm est éventuellement substitué par un ou plusieurs substituants, chacun étant indépendamment un atome d'halogène, un groupe - (alkyle en C1-6),
    - (halogénoalkyle en C1-6), O- (alkyle en C1-6),
    -O- (halogénoalkyle en C1-6), oxo, aryle,
    - (alkyle en C1-6)-aryle, -C (=O) -aryle, -CO2-aryle,
    -CO2- (alkyle en C1-6) -aryle, un cycle hétérocyclique à 5 ou 6 chaînons saturés contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S, ou un cycle hétéroatomatique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; et
    chaque n est indépendamment un nombre entier égal à zéro, 1 ou 2 ;
    ou l'un de ses sels pharmaceutiquement acceptables.
  2. Composé selon la revendication 1, dans lequel R1 représente :
    (1) -H
    (2) un groupe - (alkyle en C1-4), qui est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un atome d'halogène, un groupe -OH, -CN, - 0(alkyle en C1-4), -O (halogénoalkyle en C1-4), -C (=O) Ra, - CO2Ra, -SRa, -S(=O)Ra, -N(RaRb), -C (=O) - (alkyle en C0-4)-N (RaRb),N(Ra)-C(=O)-(alkyle C0-4) -N (RbRc) -SO2Ra, - N (Ra) SO2Rb, -SO2N (RaRb) , -N (Ra) -C (=O) Rb,
    Figure imgb0173
     N(Ra)C(=O)Rk ou -N(Ra)C(=O)C(=O)N(RbR6),
    (3) -Rk
    (4) -un groupe - (alkyle en C1-4) -Rk, dans lequel :
    (i) le groupe alkyle est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un atome d'halogène, -OH, -CN, -O(alkyle en C1-4),
    -O-(halogénoalkyle en C1-4), -N(RaRb), -N (Ra) CO2Rb,
    -N (Ra) C (=O) (alkyle en C0-4) -N (RbRc) , ou -N(Ra)-(CH2)2-4-OH ; et
    (ii) le groupe alkyle est éventuellement monosubstitué par un groupe -Rs, N (Ra) -C (=O) - (alkyle en C0-4) -Rs, -N (Ra) - (alkyle en C0-4) -Rs, O- (alkyle en C0-4) -R5, ou -N (Ra) -C (=O) - (alkyle en C0-4)-Rs ; où Rs représente
    (a) un groupe aryle qui est éventuellement substitué par 1 à 3 substituants dont chacun est indépendamment un atome d'halogène, -OH, un groupe -(alkyle en C1-4), -(alkyle en C1-4) -ORa, - (halogénoalkyle en C1-4), -0- (alkyle en C1-4), -0-(halogénoalkyle en C1-4), méthylènedioxy attaché à deux atomes de carbone adjacents, ou phényle ;
    (b) un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, 0 et S ; dans lequel le cycle hétéroaromatique est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome d'halogène, un groupe - (alkyle en C1-4) , - (alkyle en C1-4) -ORa, - (halogénoalkyle en C1-4), -O-(alkyle en C1-4) , -O- (halogénoalkyle en C1-4), oxo ou phényle ; ou
    (c) un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; le cycle hétérocyclique saturé étant éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome d'halogène, un groupe -(alkyle en C1-4), -(alkyle en C1-4)-ORa, -(halogénoalkyle en C1-4), -O- (alkyle en C1-4), -O-(halogénoalkyle en C1-4), -C(=O) Ra, -CO2Ra, C(=O)-(alkyle en C0-4)-N(RaRb), -SO2Ra, oxo, ou phényle ; ou
    (5) un groupe -(CH2)0-3-C(=O)N(Ra)-(CH2)0-3-Rk
    ou l'un de ses sels pharmaceutiquement acceptables.
  3. Composé selon la revendication 2, dans lequel R1 représente :
    (1) -H
    (2) un groupe -(alkyle en C1-4), qui est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome d'halogène, un groupe -O(alkyle en C1-4), -O (halogénoalkyle en C1-4), -C (=O) Ra, -CO2Ra, -N (RaRb) , -C (=O) -CH2)0-2-N (RaRb),
    (3) -Rk
    (4) -un groupe -(CH2)1-4-Rk, dans lequel :
    (i) le groupe -(CH2)1-4 est éventuellement substitué par 1 ou 2 substituants, chacun étant indépendamment un atome d' halogène, -OH, un groupe -O (alkyle en C1-4) , -O-(halogénoalkyle en C1-6), ou -N (RaRb) ; et
    (ii) le groupe -(CH2)1-4- est éventuellement monosubstitué par un groupe -Rs ou -N (Ra) - (CH2)1-2-Rs ; où Rs représente
    (a) un groupe phényle qui est éventuellement substitué par 1 à 3 substituants dont chacun est indépendamment un atome d'halogène, un groupe - (alkyle en C1-4), -(alkyle en C1-4)-ORa, - (halogénoalkyle en C1-4), -O-(alkyle en C1-4) ou -O-(halogénoalkyle en C1-4) ; ou
    (b) un cycle hétéroaromatique saturé à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; lequel cycle hétéroaromatique est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome d'halogène, un groupe - (alkyle en C1-4), -(alkyle en C1-4)-ORa, -(halogénoalkyle en C1-4), -O- (alkyle en C1-4), -O- (halogénoalkyle en C1-4) ; ou
    (c) un cycle hétérocyclique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; lequel cycle hétérocyclique saturé est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome d'halogène, un groupe -(alkyle en C1-4), - (alkyle en C1-4) -ORa, - (halogénoalkyle en C1-4), -O-(alkyle en C1-4), -O- (halogénoalkyle en C1-4), -C(=O)Ra ou -CO2Ra ;
    (5) un groupe -C (=O) N (Ra) - (CH2) 0-3-Rk;
    (6) un groupe -C (CH3) 2N (Ra) C (=O) Rb;
    (7) un groupe -C (CH3) 2N(Ra) C (=O) Rk; ou
    (8) un groupe -C (CH3) 2N (Ra) C (=O) C (=O) N (RbRc);

    ou l'un de ses sels pharmaceutiquement acceptables.
  4. Composé selon l'une quelconque des revendications précédentes dans lequel Rk représente un groupe cycloalkyle en C3-8, un groupe aryle choisi parmi un groupe phényle et un groupe naphtyle ; un carbocycle bicyclique choisi parmi un groupe indényle et un groupe tétrahydronaphtyle ; un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; ou un hétérocycle bicyclique qui est un cycle benzène condensé avec un cycle hétérocyclique saturé ou insaturé à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes indépendamment choisis parmi N, O et S ;
    dans lequel le groupe cycloalkyle, aryle, le carbocycle bicyclique, le cycle hétérocyclique saturé, le cycle hétéroaromatique ou l'hétérocycle bicyclique est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment
    (1) un atome d'halogène,
    (2) -OH
    (3) -CN,
    (4) un groupe -(halogénoalkyle en C1-4)
    (5) un groupe -(alkyle en C1-4), qui est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un groupe -OH, -CN, -O(alkyle en C1-4), -O (halogénoalkyle en C1-4), -C (=O) Ra, -CO2Ra, -SRa, -S (=O) Ra, -N (RaRb),-C (=O) - (CH2) 0-2N (RaRb), N (Ra) -C (=O) - (CH2) 0-2N (RbRc), -SO2Ra, -N (Ra) SO2Rb, -SO2N (RaRb) , ou N (Ra) -C (Rb) =O,
    (6) un groupe -O-(halogénoalkyle en C1-4)
    (7) un groupe -0-(alkyle en C1-4) qui est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un groupe -OH, -CN, -O (alkyle en C1-6), -O (halogénoalkyle en C1-6), -C (=O) Ra, -CO2Ra, -SRa, -S (=O) Ra, -N (RaRb), -C(=O)-(CH2)0-2N(RaRb), N (Ra) -C (=O) - (CH2) 0-2N (RbRc) , -SO2Ra, -N (Ra) SO2Rb, -SO2N(RaRb), ou N (Ra) -C (Rb) =O,
    (8) -NO2
    (9) un groupe oxo,
    (10) -C (=O) Ra,
    (11) -CO2Ra,
    (12) -SRa,
    (13) -S(=O)Ra,
    (14) -N(RaRb),
    (15) -C (=O) N (RaRb),
    (16) -C (=O) - (alkyle en C1-6) -N (RaRb),
    (17) -N(Ra)C(=O)Rb
    (18) -SO2Ra
    (19) -SO2N (RaRb),
    (18) -N (Ra) SO2Rb
    (20) -Rm
    (21) un groupe (alkyle en C1-4)-Rm,
    (22) un groupe - (CH2) 0-2-N (Ra) - (CH2) 0-2-Rm
    (23) un groupe - (CH2)0-2-O- (CH2)0-2-Rm
    (24) un groupe -(CH2)0-2-S-(CH2)0-2-Rm
    (25) un groupe -(CH2)0-2 -C (=O) - (CH2) 0-2-Rm
    (26) un groupe -C(=O)-O-(CH2)0-2-Rm
    (27) un groupe -C(=O)N(Ra)-Rm, ou
    (28) un groupe -C (=O) -C (=O) -N (RaRb),

    ou l'un de ses sels pharmaceutiquement acceptable.
  5. Composé selon la revendication 4, dans lequel chaque Rm représente indépendamment un groupe cycloalkyle en C3-7, un groupe aryle choisi parmi un groupe phényle et un groupe naphtyle ; un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S, où chaque N est éventuellement oxydé pour former un N-oxyde ; ou un hétérocycle bicyclique qui est un cycle benzène condensé avec un cycle hétérocyclique saturé ou insaturé à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes indépendamment choisis parmi N, O et S ;
    dans lequel le groupe cycloalkyle ou aryle défini par Rm est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un atome d'halogène, un groupe - (alkyle en C1-4), -(halogénoalkyle en C1-4), O-(alkyle en C1-4), -O- (halogénoalkyle en C1-4), -N (RaRb), phényle ou - (CH2)1-2-phényle ;
    le cycle hétérocyclique saturé défini dans Rm est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un groupe - (alkyle en C1-4) éventuellement substitué par un groupe -O- (alkyle en C1-4), - (halogénoalkyle en C1-4), O- (alkyle en C1-4), -O-(halogénoalkyle en C1-4), oxo, phényle, -(CH2)1-2-phényle, -C(=O)-phényle, -CO2-phényle, -CO2- (CH2)1-2-phényle ou un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant 1 à 4 hétéroatomes indépendamment choisis parmi N, 0 et S ou un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S ; et le cycle hétéroaromatique ou l'hétérocycle bicyclique défini dans Rm est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un atome d'halogène, un groupe -(alkyle en C1-4), -(halogénoalkyle en C1-4), O- (alkyle en C1-4), -O- (halogénoalkyle en C1-4), oxo, phényle, ou -(CH2)1-2-phényle ;
    ou l'un de ses sels pharmaceutiquement acceptable.
  6. Composé selon la revendication 4, dans lequel Rk représente un groupe phényle ; un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant 1 ou 2 hétéroatomes choisis parmi 1 ou 2 atomes de N, 0 ou 1 atome d'O, et 0 ou 1 atome de S ; un cycle hétéroaromatique à 5 ou 6 chaînons contenant 1 ou 2 hétéroatomes choisis parmi 1 ou 2 atomes de N, ou 1 atome d'O et 0 ou 1 atome de S ; ou un hétérocycle bicyclique qui est un cycle benzène condensé avec un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant 1 ou 2 atomes d'azote ; dans lequeel :
    (a) le groupe phényle, le cycle hétérocyclique saturé, le cycle hétéroaromatique ou l'hétérocycle bicyclique est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment
    (1) un atome de fluor,
    (2) un atome de chlore,
    (3) un atome de brome,
    (4) -OH
    (5) -CF3,
    (6) un groupe - (alkyle en C1-4), qui est éventuellement substitué par 1 ou 2 substituants, chacun étant indépendamment -O, -CN, -O-(alkyle en C1-4), OCF3, -N(RaRb), -C(=O)N(RaRb), ou N(Ra)-C(=O)- (CH2)0-2N (RbRc),
    (7) -OCF3,
    (8) un groupe -O-(alkyle en C1-4)
    (9) -C(=O)Ra,
    (10) -CO2Ra,
    (11) SRa,
    (12) -SRa,
    (13) -N(RaRb),
    (14) -C(=O)N(RaRb),
    (15) -C (=O) - (CH2) 1-2-N (RaRb) ,
    (16) -N(Ra)C(=O)Rb, ou
    (17) -SO2Ra,
    (b) le groupe phényle est éventuellement monosubstitué par
    (1) - (CH2 )1-2-Rm ou
    (2) - ( CH2 )0-2-N (Ra) - (CH2) 0-2-Rm ; et
    (c) le cycle hétérocyclique saturé, le cycle hétéroaromatique, ou l'hétérocycle bicyclique est éventuellement mono- ou disubstitué par un groupe
    (1) oxo
    (2) - (CH2) 1-2-Rm
    (3) -O- (CH2)1-2-Rm
    (4) - (CH2)0-1-C(=O) - (CH2)0-2-Rm ;
    ou l'un de ses sels pharmaceutiquement acceptables.
  7. Composé selon la revendication 6, dans lequel chaque Rm représente indépendamment un groupe cyclopropyle ; phényle ; un cycle hétérocyclique saturé à 5 ou 6 chaînons choisi parmi les groupes pyrrolidinyle, imidazolidinyle, pyrazolidinyle, pipéridinyle, pipérazinyle et morpholinyle ; ou un cycle hétéraromatique à 5 ou 6 chaînons choisi parmi les groupes thiényle, pyridyle éventuellement sous la forme d'un N-oxyde, imidazolyle, pyrrolyle, pyrazolyle, thiazolyle, isothiazolyle, oxazolyle, isooxazolyle, oxadiazolyle, thiadiazolyle, pyrazinyle, pyrimidinyle, triazolyle, tétrazolyle, furanyle et pyridazinyle ; où
    le groupe cyclopropyle est non substitué.
    le groupe phényle est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome d'halogène, un groupe - (alkyle en C1-4), -CF3, -O- (alkyle en C1-4), -OCF3, ou N(RaRb);
    le cycle hétérocyclique saturé est éventuellement substitué par 1 ou 2 substituants chacun étant indépendamment un groupe - (alkyle en C1-4), -CF3, -O- (alkyle en C1-4), -OCF3, oxo, phényle - (CH2)1-2-phényle, -C (=O) -phényle, -CO2-phényle, ou -CO2-CH2-phényle ; et
    le cycle hétéroaromatique est éventuellement substitué par 1 ou 2 substituants, chacun étant indépendamment un groupe -(alkyle en C1-4), -CF3, -O- (alkyle en C1-4), -OCF3, oxo, phényle ou - (CH2)1-2-phényle
    ou l'un des sels pharmaceutiquement acceptables.
  8. Composé selon l'une quelconque des revendications précédentes, dans lequel R2 représente :
    (1) un groupe - (alkyle en C1-6),
    (2) un groupe (alkyle en C1-6) substitué par -N (RaRb), sous réserve que -N(RaRb) ne soit pas attaché à l'atome de carbone dans le groupe -(alkyle en C1-6) qui est attaché à l'atome d'azote du cycle ;
    (3) un groupe -(alkyle en C1-6) substitué par un groupe phényle, lequel groupe phényle est :
    (a) éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un atome d'halogène, un groupe - (alkyle en C1-4), -(halogénoalkyle en C1-4), -O- (alkyle en C1-4), -O-halogénoalkyle en C1-4) ou - (alkyle en C0-4)-N (RaRb) ; et
    (b) éventuellement monosubstitué par un groupe -(alkyle en C1-4) substitué par un cycle hétérocyclique saturé à 5 ou 6 chaînons, contenant de 1 à 3 hétéroatomes choisis parmi 1 ou 2 atomes de N, 0 ou 1 atome de O et 0 ou 1 atome de S ; le cycle hétérocyclique étant éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un groupe -(alkyle en C1-6), oxo, ou un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes choisis parmi 1 à 3 atomes de N, 0 ou 1 atome d'O et 0 ou 1 atome de S ; ou
    (4) un groupe - (alkyle en C1-6) éventuellement substitué par -OH et substitué par un hétérocycle monocyclique saturé à 5 ou 6 chaînons, qui contient de 1 à 3 hétéroatomes choisis parmi 1 à 3 atomes de N, 0 ou 1 atome d'O, et 0 ou 1 atome de S ; lequel hétérocycle est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un groupe - (alkyle en C1-6), -O- (alkyle en C1-6), oxo ou phényle ; ou
    (5) un groupe -(alkyle en C1-6) substitué par un cycle hétéroaromatique à 5 ou 6 chaînons qui contient de 1 à 3 hétéroatomes choisis parmi 1 à 3 atomes de N, 0 ou 1 atome de O, et 0 ou 1 atome de S ; le cycle hétéroaromatique étant éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un groupe -(alkyle en C1-6), -0-(alkyle en C1-6), oxo ou phényle ;
    ou l'un de ses sels pharmaceutiquement acceptables.
  9. Composé selon la revendication 8, dans lequel R2 représente un groupe méthyle ; ou l'un de ses sels pharmaceutiquement acceptables.
  10. Composé selon l'une quelconque des revendications précédentes, dans lequel R3 représente -H ou un groupe - (alkyle en C1-4) ; ou l'un de ses sels pharmaceutiquement acceptables.
  11. Composé selon la revendication 10, dans lequel R3 représente -H ou un groupe méthyle ; ou l'un de ses sels pharmaceutiquement acceptables.
  12. Composé selon la revendication 11, dans lequel R3 représente -H ; ou l'un de ses sels pharmaceutiquement acceptables.
  13. Composé selon l'une quelconque des revendications précédentes, dans lequel R4 représente un groupe alkyle en C1-4 substitué par un groupe aryle, qui est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un atome d'halogène, un groupe -OH, -(alkyle en C1-4),-(alkyle en C1-4)-ORa, -(halogénoalkyle en C1-4), - O-(alkyle en C1-4), -O-(halogénoalkyle en C1-4), -CN, -NO2, - N(RaRb), - (alkyle en C1-4)-N(RaRb) , -C(=O)N(RaRb), -C(=O)Ra, CO2Ra, - (alkyle en C1-4)-CO2Ra, -OCO2Ra, -SRa, -S(=O)Ra, - SO2Ra, -N(Ra) SO2Rb,
    -SO2N(RaRb), -N(Ra)C(=O)Rb, -N(Ra)CO2Rb, - (alkyle en C1-4)-N(Ra)CO2Rb, méthylènedioxy attaché à deux atomes de carbone adjacents du cycle, phényle, -phényl-(alkyle en C1-4), -0-phényle ou - (CH2)0-2-het ;
    où het représente un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes indépendamment choisis parmi N, O et S, et het est éventuellement condensé avec un cycle benzène, et est éventuellement substitué par un ou deux substituants, chacun étant indépendamment un groupe -(alkyle en C1-4), -(halogénoalkyle en C1-4), -O-(alkyle en C1-4), -O-(halogénoalkyle en C1-4), ou CO2Ra ;
    ou l'un de ses sels pharmaceutiquement acceptables.
  14. Composé selon la revendication 13, dans lequel R4 représente un groupe -CH2-phényle, dans lequel le groupe phényle est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome de fluor, de brome, de chlore, un groupe -OH, (alkyle en C1-4), - (fluoroalkyle en C1-4), -0-(alkyle en C1-4), -0-(fluoroalkyle en C1-4) , - (CH2) 1-2-N (RaRb) , -SO2Ra, - (CH2)0-2-CO2Ra, - (CH2)0-2-N (Ra) -CO2Rb, NO2, SRa, -N (RaRb) ou phényle ; et chacun des Ra et Rb représente indépendamment H ou un groupe alkyle en C1-4 ;
    ou l'un de ses sels pharmaceutiquement acceptables.
  15. Composé selon la revendication 14, dans lequel R4 représente un groupe -CH2-phényle, dans lequel le groupe phényle est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment -F, -Br, -Cl, un groupe -OH, (alkyle en C1-4), -(fluoroalkyle en C1-4) -0-(alkyle en C1-4), -SO2- (alkyle en C1-4), -S- (alkyle en C1-4), -N(CH3)2, ou -O- (fluoroalkyle en C1-4) ;
    ou l'un de ses sels pharmaceutiquement acceptable.
  16. Composé selon la revendication 15, dans lequel R4 représente un groupe p-fluorobenzyle ou 2,3-diméthoxybenzyle ;
    ou l'un de ses sels pharmaceutiquement acceptables.
  17. Composé selon la revendication 1, dans lequel :
    R1 représente Rk ;
    Rk représente un groupe phényle qui est
    (a) éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment
    (1) un atome d'halogène,
    (2) un groupe -(alkyle en C1-6), qui est éventuellement substitué par 1 ou 2 substituants, chacun étant indépendamment un groupe -O (alkyle en C1-6), -O (halogénoalkyle en C1-6), -C (=O) Ra, -CO2Ra, -SRa, -S (=O) Ra, -N (RaRb) , -C (=O) - (CH2) 0-2N (RaRb) , N (Ra) -C (=O) - (CH2) 0-2N (RaRb) , -SO2Ra, -N (Ra) SO2Rb, -SO2N (RaRb) , Ou N (Ra) -C (Rb) =O,
    (3) un groupe halogénoalkyle en C1-6
    (4) un groupe -O- (halogénoalkyle en C1-6),
    (5) -C (=O) Ra,
    (6) -CO2Ra,
    (7) -C (=O ) N (RaRb), ou
    (8) -C (=O) - (alkyle en C1-6) -N (RaRb), et
    (b) éventuellement monosubstitué par
    (1) un groupe - (alkyle en C1-4) -Rm, ou
    (2) un groupe - (alkyle en C0-4)-N (Ra) - (alkyle en C0-4) -Rm; où Rm est un groupe aryle choisi parmi un groupe phényle et naphtyle ; un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes indépendamment choisi parmi N, O et S ; ou un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes indépendamment choisis parmi N, O et S ; ou
    le groupe aryle défini dans Rm est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome d'halogène, un groupe - (alkyle en C1-4), -CF3, -0-(alkyle en C1-4), OCF3, ou -N (RaRb) ;
    le cycle hétérocyclique saturé défini dans Rm est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un groupe -(alkyle en C1-4), ou oxo, et est éventuellement monosubstitué par un groupe phényle, - (CH2)1-2-phényle, -C(=O)-phényle, -CO2-phényle, -CO2- (CH2)1-2-phényle ou un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes indépendamment choisis parmi N, O et S ; et
    le cycle hétéroaromatique défini dans Rm est éventuellement substitué par 1 ou 2 substituants, chacun étant indépendamment un groupe -(alkyle en C1-4) ou oxo ;

    ou l'un de ses sels pharmaceutiquement acceptables.
  18. Composé selon la revendication 17, dans lequel
    R2 représente un groupe méthyle ;
    R3 représente -H ;
    R4 représente :
    (1) un groupe -CH2-phényle, dans lequel le groupe phényle est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome de fluor, de brome, de chlore, un groupe -OH, (alkyle en C1-4), -(fluoroalkyle en C1-4) -O-(alkyle en C1-4), -O-(fluoroalkyle en C1-4), -(CH2)1-2-N (RaRb), -SO2Ra, - (CH2)0-2-CO2 (Ra), - (CH2)0-2-N (Ra)CO2Rb, -NO2, SRa, -N(RaRb) ou phényle ; ou
    (2) un carbocycle bicyclique condensé choisi parmi
    Figure imgb0174
    Figure imgb0175

    dans lesquels Z1 représente -H ou -OH ; et chaque Ra et Rb représente indépendamment H ou un groupe - (alkyle en C1-4),
    ou l'un de ses sels pharmaceutiquement acceptables.
  19. Composé selon la revendication 18, dans lequel R4 représente un groupe 4-fluorobenzyle ou 2,3-diméthoxybenzyle ;
    ou l'un de ses sels pharmaceutiquement acceptables.
  20. Composé selon la revendication 1, qui est un composé de formule (II) :
    Figure imgb0176
    dans laquelle
    Q représente :
    (1) un groupe méthyle qui est éventuellement substitué par 1 ou 2 groupes -O- (alkyle en C1-4),
    (2) un groupe phényle qui est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment -F, -Cl, -Br, un groupe - (alkyle en C1-4), -CF3, -O- (alkyle en C1-4), -OCF3, méthylènedioxy attaché à deux atomes de carbone adjacents, ou phényle, ou
    (3) un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant 1 à 3 hétéroatomes indépendamment choisis parmi N, O et S ; lequel cycle hétérocyclique saturé est éventuellement substitué par 1 ou 2 substituants, chacun étant indépendamment -F, -Cl, -Br, un groupe -(alkyle en C1-4), oxo, phényle ou -C(=O)-phényle ;
    T représente :
    (1) -H
    (2) -OH,
    (3) un groupe méthyle ou éthyle, éventuellement substitué par -OH ou un groupe -O-(alkyle en C1-4),
    (4) un groupe -O-(alkyle en C1-4),
    (5) -N (RaRb) ,
    (6) -N (Ra) - (CH2) 2-OH,
    (7) -N(Ra) -CO2Rb,
    (8) -N (Ra) -C (=O) - (CH2) 1-2-N (RaRb) ,
    (9) -Rs,
    (10) -(CH2)1-2-Rs, ou
    (11) -(CH2)0-2-N(Ra)-(CH2)0-3-Rs ;
    Rs représente :
    (1) un groupe phényle éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un atome d'halogène, un groupe -(alkyle en C1-4), (alkyle en C1-4)-ORa, - (halogénoalkyle en C1-4), -O- (alkyle en C1-4), -O- (halogénoalkyle en C1-4), ou N (RaRb) ;
    (2) un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes indépendamment choisis parmi N, O et S ; qui est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un groupe - (alkyle en C1-4), (alkyle en C1-4)-ORa,- (halogénoalkyle en C1-4), -0- (alkyle en C1-4), -O- (halogénoalkyle en C1-4), -C(=O)Ra, oxo, phényle ou -CH2-phényle ; ou
    (3) un cycle hétéroaromatique à 5 ou 6 chaînons contenant 1 à 3 hétéroatomes indépendamment choisis parmi N, O et S ; qui est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un groupe -(alkyle en C1-4), -(alkyle en C1-4) -ORa, - (halogénoalkyle en C1-4), -O- (alkyle en C1-4), -O- (halogénoalkyle en C1-4), ou oxo ;
    R2 représente :
    (1) un groupe - (alkyle en C1-4) ,
    (2) un groupe - (alkyle en C1-4) substitué par -N (RaRb) , sous réserve que -N (RaRb) ne soit pas attaché à l'atome de carbone dans le groupe - (alkyle en C1-4) qui est attaché à l'atome d'azote du cycle, ou
    (3) un groupe -(alkyle en C1-4) substitué par un hétérocycle monocyclique saturé à 5 ou 6 chaînons qui contient de 1 à 3 substituants choisis parmi 1 à 3 atomes de N, 0 ou 1 atome d'O, et 0 ou 1 atome de S ; l'hétérocycle saturé étant éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un groupe - (alkyle en C1-4) ;
    R3 représente -H ou un groupe - (alkyle en C1-4),
    R4 représente un groupe -CH2-phényle, lequel groupe phényle est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome de fluor, de brome, de chlore, un groupe -OH, - (alkyle en C1-4), -(fluoroalkyle en C1-4) -O- (alkyle en C1-4), -O- (fluoroalkyle en C1-4), - (CH2)-1-2-N (RaRb) , -SO2Ra, - (CH2)0-2-CO2Ra, - (CH2)0-2-N (Ra) -CO2Rb, -NO2, SRa, -N (RaRb) ou phényle ;
    et chacun des Ra et Rb représente indépendamment H ou un groupe alkyle en C1-4;
    s représente un nombre entier égal à zéro, 1 ou 2 ;

    ou l'un de ses sels pharmaceutiquement acceptables.
  21. Composé selon la revendication 20, dans lequel
    Q représente un groupe phényle;
    T représente :
    (1) -H
    (2) -N (RaRb) ,
    (3) un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes indépendamment choisis parmi N, O et S ; qui est éventuellement substitué par 1 ou 2 substituants, chacun étant indépendamment un groupe - (alkyle en C1-4) ou -C(=O)Ra, ou
    (4) un groupe -N(Ra)-(CH2)1-2-(cycle hétéroaromatique), dans lequel le cycle hétéroaromatique est un cycle à 5 ou 6 chaînons contenant 1 ou 2 atomes de N ;
    R2 représente un groupe méthyle ;
    R3 représente -H ; et
    R4 représente un groupe -CH2-phényle, dans lequel le groupe phényle est éventuellement substitué par 1 à 2 substituants, chacun étant indépendamment -F, -Br, -Cl, un groupe - (alkyle en C1-4), -CF3, -O- (alkyle en C1-4), -SO2CH3, -SCH3, N(CH3)2 ou -OCF3 ;
    et chaque Ra et Rb représente indépendamment un groupe -H, méthyle, ou éthyle ; et
    s représente un nombre entier égal à zéro ou 1 ;

    ou l'un de ses sels pharmaceutiquement acceptables.
  22. Composé selon la revendication 1, dans lequel
    R1 représente -Rk ;
    Rk représente (i) un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant de 0 à 1 atome d'oxygène et de 1 à 3 atomes d'azote ou (ii) un hétérocycle bicyclique qui est un cycle benzène condensé avec un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant de 0 à 1 atome d'oxygène et de 1 à 3 atomes d'azote ;
    le cycle hétérocyclique saturé ou l'hétérocycle bicyclique étant éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment
    (1) un groupe -(alkyle en C1-4) qui est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un atome d'halogène, un groupe -O (alkyle en C1-4), -O- (halogénoalkyle en C1-4), -C (=O) Ra, -CO2Ra, -SRa, -S (=O) Ra, -N (RaRb) , -C (=O) - (CH2)0-2-N (RaRb) , -N (Ra) -C (=O) - (CH2)0-2-N(RbRc) , -SO2Ra, -N(Ra)SO2Rb, -SO2N(RaRb) , ou -N (Ra)-C(Rb)=O,
    (2) -OH
    (3) -C(=O)Ra,
    (4) -CO2Ra,
    (5) -C (=O) N (RaRb),
    (6) -C (=O) - (alkyle en C1-6) -N (RaRb) ,
    (7) -SRa,
    (8) -S(=O)Ra,
    (9) -SO2Ra,
    (10) -N(RaRb),
    (11) -Rm,
    (12) un groupe-(alkyle en C1-4)-Rm, le groupe alkyle étant éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un atome d'halogène, un groupe -OH, -CN, - (halogénoalkyle en C1-4), -0- (alkyle en C1-4), -O-(halogénoalkyle en C1-4), -C(=O)Ra, -CO2Ra, -SRa, -S(=O)Ra, -N (RaRb), -N (Ra) CO2Rb, -SO2Ra, -N(Ra) SO2Rb, -SO2N (RaRb), ou -N(Ra)-C(Rb)=O,
    (13) un groupe - (alkyle en C0-4)-N(Ra) - (alkyle en C0-4) -Rm
    (14) un groupe -(alkyle en C0-4)-O-(alkyle en C0-4)-Rm
    (15) un groupe -(alkyle en C0-4)-S-(alkyle en C0-4)-Rm
    (16) un groupe - (alkyle en C0-4) -C (=O) - (alkyle en C0-4) -Rm
    (17) un groupe -C (=O) -O- (alkyle en C0-4) -Rm, ou
    (18) un groupe -C(=O)-N(Ra)- (alkyle en C0-4) -Rm
    chaque Rm représentant indépendamment un groupe
    -(cycloalkyle en C3-6) ; un groupe aryle choisi parmi un groupe phényle et un groupe naphtyle ; un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant 1 à 3 hétéroatomes indépendamment choisis parmi N, 0 et S ; ou un cycle hétéroaromatique à 5 ou 6 chaînons contenant 1 à 3 hétéroatomes indépendamment choisis parmi N, O et S, chaque N étant éventuellement oxydé pour former un N-oxyde ; ou le groupe aryle est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome d'halogène, un groupe - (alkyle en C1-4), -CF3, -O- (alkyle en C1-4) , -OCF3, ou -N(RaRb) ;
    le cycle hétérocyclique saturé étant éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un groupe -(alkyle en C1-4) ou oxo, et étant en outre éventuellement monosubstitué par un groupe phényle, -(CH2)1-2-phényle, -C(=O)-phényle, -CO2-phényle, -CO2-(CH2)1-2-phényle ; et
    le cycle hétéroaromatique étant éventuellement substitué par 1 ou 2 substituants, chacun étant éventuellement un atome d'halogène, un groupe -(alkyle en C1-4), ou oxo ;

    ou l'un de ses sels pharmaceutiquement acceptables.
  23. Composé selon la revendication 22, dans lequel
    R1 représente :
    Figure imgb0177
    Figure imgb0178
    Figure imgb0179
    R8 représente :
    (1) -H
    (2) un groupe -(alkyle en C1-4), qui est éventuellement substitué par 1 ou 2 substituants, chacun étant indépendamment un groupe -OH, -O- (alkyle en C1-4), -OCF3, -C (=O) Ra, -CO2Ra, -SRa, -N (RaRb) ou -C (=O) N (RaRb) ,
    (3) -C (=O) Ra,
    (4) -CO2Ra,
    (5) -C (=O) N(RaRb),
    (6) -C (=O) - (CH2)1-2-N (RaRb),
    (7) -SO2Ra,
    (8) -(CH2)1-2-Rm,
    (9) -(CH2)0-2-C (=O) - (CH2)0-2-Rm,
    (10) -C (=O) -O- (CH2)0-2-Rm, ou
    (11) -C (=O) N(Ra)-(CH2)0-2-Rm ;
    R10 représente -H, -OH, un groupe - (alkyle en C1-4), -O-(alkyle en C1-4), -N(RaRb), ou -O- (CH2)1-2-Rm ;
    R12 représente
    (1) -H
    (2) -un groupe -(alkyle en C1-4) qui est éventuellement substitué par 1 ou 2 substituants, chacun étant indépendamment un groupe -OH, O- (alkyle en C1-4), -OCF3, -C(=O)Ra, -CO2Ra, -SRa, -N (RaRb) ou -C (=O) N (RaRb) ;
    (3) -C(=O)Ra,
    (4) -CO2Ra,
    (5) -C(=O)-(CH2)1-2-N(RaRb), ou
    (6) -SO2Ra ;
    R2 représente un groupe méthyle ;
    R3 représente -H ou un groupe méthyle ;
    R4 représente un groupe -CH2-phényle, dans lequel le groupe phényle est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome de fluor, de brome, de chlore, un groupe -OH, - (alkyle en C1-4), -(fluoroalkyle en C1-4) -O-(alkyle en C1-4),
    -O- (fluoroalkyle en C1-4), -(CH2)-1-2-N(RaRb), -SO2Ra, -(CH2)0-2-CO2Ra, - (CH2) 0-2-N (Ra) CO2Rb, -NO2, -SRa, -N (RaRb) ou phényle ; et
    chaque Ra et Rb représente indépendamment -H ou un groupe -(alkyle en C1-4) ;
    ou l'un de ses sels pharmaceutiquement acceptable.
  24. Composé selon la revendication 1, qui est un composé de formule (III) :
    Figure imgb0180
    où R2 représente :
    (1) un groupe - (alkyle en C1-6),
    (2) un groupe - (alkyle en C1-6) substitué par -N (RaRb) sous réserve que -N (RaRb) ne soit pas attaché à l'atome de carbone dans le groupe - (alkyle en C1-6) qui est attaché à l'atome d'azote du cycle ;
    (2) un groupe - (alkyle en C1-6) substitué par un groupe phényle, qui est :
    (a) éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un atome d'halogène, un groupe - (alkyle en C1-4), - (halogénoalkyle en C1-4), -O- (alkyle en C1-4), -O- (halogénoalkyle en C1-4) ou - (alkyle en C0-6) - N (RaRb) ; et
    (b) éventuellement monosubstitué par un groupe -(alkyle en C1-4) substitué par un cycle hétérocyclique saturé à 5 ou 6 chaînons, contenant 1 à 3 hétéroatomes choisis parmi 1 ou 2 atomes de N, 0 ou 1 atome d'O et 0 ou 1 atome de S ;
    lequel cycle hétérocyclique est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un groupe -(alkyle en C1-6), oxo, ou un cycle hétéroaromatique à 5 ou 6 chaînons contenant 1 à 3 hétéroatomes choisis parmi 1 à 3 atomes de N, 0 ou 1 atome d'O et 0 ou 1 atome de S ; ou
    (4) un groupe - (alkyle en C1-6) éventuellement substitué par -OH et substitué par un hétérocycle monocyclique saturé à 5 ou 6 chaînons, qui contient de 1 à 3 hétéroatomes choisis parmi 1 à 3 atomes de N, 0 ou 1 atome d'O, et 0 ou 1 atome de S ; lequel hétérocycle est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un groupe - (alkyle en C1-6), -O- (alkyle en C1-6), oxo ou phényle ; ou
    (5) un groupe -(alkyle en C1-6) substitué par un cycle hétéroaromatique à 5 ou 6 chaînons qui contient de 1 à 3 hétéroatomes choisis parmi 1 à 3 atomes de N, 0 ou 1 atome de O, et 0 ou 1 atome de S ; lequel cycle hétéroaromatique est éventuellement substitué par 1 à 4 substituants, chacun étant indépendamment un groupe -(alkyle en C1-6), -O-(alkyle en C1-6), oxo ou phényle ;

    ou l'un de ses sels pharmaceutiquement acceptables.
  25. Composé selon la revendication 24, dans lequel
    R2 représente :
    (1) un groupe -(alkyle en C1-4),
    (2) un groupe -(CH2)2-3-N(RaRb),
    (3) un groupe - (CH2) 1-3-phényle, dans lequel le groupe phényle est :
    (a) éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome de fluor, de chlore, de brome, un groupe - (alkyle en C1-4), -CF3, -O- (alkyle en C1-4) , -O-CF3, ou - (CH2)1-3-N (RaRb) ; et
    (b) éventuellement monosubstitué par un groupe-(CH2)1-3-(hétérocycle saturé) qui est un cycle hétérocyclique saturé à 5 ou 6 chaînons, contenant de 1 à 3 hétéroatomes choisis parmi 1 ou 2 atomes de N, 0 ou 1 atome de O et 0 ou 1 atome de S ; lequel cycle hétérocyclique est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un groupe -(alkyle en C1-4) ou pyridyle ;
    (4) un groupe -(CH2)1-3-(hétérocycle saturé), dans lequel la partie -(CH2)1-3 est éventuellement substituée par un groupe -OH et l'hétérocycle saturé est un hétérocycle monocyclique saturé à 5 ou 6 chaînons, qui contient de 1 à 3 hétéroatomes choisis parmi 1 à 3 atomes de N, 0 ou 1 atome d'O, et 0 ou 1 atome de S ; lequel hétérocycle est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un groupe -(alkyle en C1-4) ; ou
    (5) un groupe - (CH2) 1-3-pyridyle
    R3 représente -H, ou un groupe méthyle ;
    R4 représente un groupe -CH2-phényle, dans lequel le groupe phényle est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome de fluor, de brome, de chlore, un groupe -OH, -(alkyle en C1-4), -(fluoroalkyle en C1-4), -O-(alkyle en C1-4), -O-(fluoroalkyle en C1-4), - (CH2)1-2-N (RaRb), -SO2Ra, - (CH2) 0-2-CO2Ra, -(CH2)0-2-N(Ra)CO2Rb, -NO2, SRa -N (RaRb) ou phériyle ; et
    chaque Ra et Rb représente indépendamment -H ou un groupe - (alkyle en C1-4) ;
    ou l'un de ses sels pharmaceutiquement acceptable.
  26. Composé selon la revendication 1, dans lequel
    R1 représente -C (=O) NH- (CH2)1-2-Rk ; et
    Rk représente (i) un cycle hétérocyclique saturé à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes indépendamment choisis parmi N, O et S, ou (ii) un cycle hétéroaromatique à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes indépendamment choisis parmi N, O et S ;
    ou l'un de ses sels pharmaceutiquement acceptables.
  27. Composé selon la revendication 26, dans lequel
    R2 représente un groupe méthyle,
    R3 représente -H ou un groupe méthyle,
    R4 représente un groupe -CH2-phényle, dans lequel le groupe phényle est éventuellement substitué par 1 à 3 substituants, chacun étant indépendamment un atome de fluor, de brome, de chlore, un groupe -OH, - (alkyle en C1-4), -(fluoroalkyle en C1-4) -0-(alkyle en C1-4),
    -O- (fluoroalkyle en C1-4), - (CH2) -1-2-N (RaRb), -SO2Ra, - (CH2) 0-2-CO2Ra, - (CH2) 0-2 -N (Ra) CO2Rb, -NO2, SRa, -N (RaRb) ou phényle ; et
    chaque Ra et Rb représente indépendamment -H ou un groupe -(alkyle en C1-4) ;
    ou l'un de ses sels pharmaceutiquement acceptable.
  28. Composé selon la revendication 1, qui est un composé choisi dans l'ensemble consistant en
    N-(2-éthoxybenzyl)-5-hydroxy-1-méthyl-2-(4-méthylphényl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(2,3-diméthoxybenzyl)-5-hydroxy-1-méthyl-2-(4-méthylphényl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(2,3-diméthoxybenzyl)-2-{4-[(diméthylamino)méthyl]phényl}-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-2-{4-[(diméthylamino)méthyl]phényl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;
    N-(2,3-diméthoxybenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[4-(pyrrolidin-1-ylméthyl)phényl]-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[4-(pyrrolidin-1-ylméthyl)phényl]1,6-dihydropyrimidine-4-carboxamide;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[4-(pipéridin-1-ylméthyl)phényl]-1,6-dihydropyrimidine-4-carboxamide ;
    N-(2,3-diméthoxybenzyl)-5-hydroxy-1-méthyl-2-[4-(morpholin)-4-ylméthyl)phényl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-[4-(morpholin-4-ylméthyl)phényl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(4-[(4-méthylpipérazin-1-yl)méthyl]phényl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{4-[(diéthylamino)méthyl]phényl}-N-(2,3-diméthoxybenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{4-[(diéthylamino)méthyl]phényl}-N-(4-fluorobenzyl)-4-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(diméthylamino)(phényl)méthyl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-2-[(4-formylpipérazin-1-yl)(phényl)méthyl]-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-(phényl [(pyridin-3-ylméthyl)amino]méthyl)-1,6-dihydropyrimidine-4-carboxamide ;
    2-benzyl-1-[2-(diméthylamino)éthyl]-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    1-[2-(diméthylamino)éthyl)-N-(4-fluorobenzyl)-5-hydroxy-2-(2-méthylphényl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(4-méthylphényl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-benzyl-N-(2,3-diméthoxybenzyl)-1-[2-(diméthylamino)éthyl]-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{4-[(4-éthylpipérazin-1-yl)méthyl]phényl)}-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-{4-[(2-pyridin-3-ylpipéridin-1-yl)méthyl]phényl}-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;
    N-(2,3-diméthoxybenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-[4-fluoro-2-(trifluorométhyl)benzyl]-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(3-chloro-4-méthylbenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    5-hydroxy-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-indèn-1-yl]-1-méthyl-2-{4-[(4-méthylpipérazin-1-yl)méthyl]phényl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-2-(4-{[(2R)-2-(méthoxyméthyl)pyrrolidin-1-yl]méthyl}phényl)-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-2-(4-{[(2S)-2-(méthoxyméthyl)pyrrolidin-1-yl]méthyl}phényl)-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-2-(4-{[(4-fluorobenzyl)amino]méthyl}phényl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-benzyl-N-(4-fluorobenzyl)-5-hydroxy-1-(2-morpholin-4-yléthyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    1-[2-(diméthylamino)éthyl]-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-(pyridin-3-ylméthyl)-1,6-dihydropyrimidine-4-carboxamide;
    2-benzyl-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-(2-pyrrolidin-1-yléthyl)-1,6-dihydropyrimidine-4-carboxamide ;
    2-benzyl-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-(2-pipéridin-1-yléthyl)-1,6-dihydropyrimidine-4-carboxamide;
    2-(1-benzylpipéridin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(1-méthylpipéridine-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-benzylpipéridin-3-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    1-(3-[(diméthylamino)méthyl]benzyl}-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(2,3-diméthoxybenzyl)-1-[2-(diméthylamino)éthyl]-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(2,3-diméthoxybenzyl)-5-hydroxy-6-oxo-1-(pyridin-3-ylméthyl)-1,6-dihydropyrimidine-4-carboxamide ;
    N4-(4-fluorobenzyl)-5-hydroxy-1-méthyl-N2-(2-morpholin-4-yléthyl)-6-oxo-2,6-dihydropyrimidine-2,4-dicarboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-[3-(pyrrolidin-1-ylméthyl)benzyl]-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-[3-(morpholin-4-ylméthyl)benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide N-(4-fluorobenzyl)-5-hydroxy-1-{3-[(4-méthylpipérazin-1-yl)méthyl]benzyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-{3-[(4-pyridin-2-ylpipérazin-1-yl)méthyl]benzyl}-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-[2-(morpholin-4-ylméthyl) benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-{2-[(4-pyridin-2-ylpipérazin-1-yl)méthyl]benzyl}-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-pyrrolidin-2-yl-1,6-dihydropyrimidine-4-carboxamide ;
    N4-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-N2-(pyridin-2-ylméthyl)-1,6-dihydropyrimidine-2,4-dicarboxamide :
    N-(4-fluorobenzyl)-5-hydroxy-1-(2-hydroxy-3-morpholin-4-ylpropyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-[4-(morpholin-4-ylméthyl)benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide; N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(2-morpholin-4-yléthyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(2,2-diméthoxyéthyl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[2-(4-benzoylpipérazin-1-yl)éthyl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[1-(N,N-diméthylglycyl)pipéridin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(1-méthyl-2,3-dihydro-1H-indol-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-(1,2,3,4-tétrahydroquinolin-2-yl)-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(1-méthyl-1,2,3,4-tétrahydroquinolin-2-yl)-6-oxo-1,6dihydropyrimidine-4-carboxamide ;
    (2S,4R)-4-(benzyloxy)-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidin-2-yl)pyrrolidine-1-carboxylate de tert-butyle ;
    (2S, 4R)-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-hydroxypyrrolidine-1-carboxylate de tert-butyle ;
    2-[(2S,4R)-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-hydroxy-1-méthylpyrrolidin-2-yl]-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2S,4R)-4-(benzyloxy)-1-méthylpyrrolidin-2-yl]-N-(4-flurobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2S,4R)-1-benzoyl-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[1-(N,N-diméthylglycyl)-2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-benzoyl-2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-2,3-dihydro-1H-indol-2-yl]-1,6-dihydropyrimidine-4-carboxamide ;
    3-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-méthylpipérazine-1-carboxylate de tert-butyle ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(4-méthylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ; (+)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(4-méthylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    (-)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(4-méthylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-éthyl-2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-benzoylpipéridin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)pipéridin-2-yl]-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(2-méthyl-1,2,3,4-tetrahydro-isoquinolin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-benzoylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl)-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(1-méthylpyrrolidin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2S, 4R)-4-(benzyloxy)-1-(pyridin-2-ylcarbonyl)pyrrolidine-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[1-(diméthylamino)-2-phényléthyl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;
    2-[(2S,4R)-1-benzoyl-4-hydroxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-2-(1-isobutyl-2,3-dihydro-1H-indol-2-yl)-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-2-(1-isopropyl-2,3-dihydro-1H-indol-2-yl)-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[1-(N,N-diméthylglycyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{1-[(6-bromopyridin-2-yl)carbonyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(1-méthylpipérazin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-benzoyl-4-méthylpipérazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[1-(pyridin-2-ylcarbonyl)-1,2,3,4-tétratrydroquinolin-2-yl]-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-acétylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[1-(cyclopropylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-[1-(méthylsulfonyl)pyrrolidin-2-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-{1-[(4-méthylmorpholin-3-yl)carbonyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyridine-4-carboxamide ;
    2-(1,4-diméthylpipérazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[1-(pyridin-3-ylcarbornyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2S,4R)-2-acétyl-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-2-(1-isonicotinoylpyrrolidin-2-yl)-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;
    2-{1-[(éthylamino)carbonyl]pyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-{1-[(1-méthyl-1H-imidazol-2-yl)carbonyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2S,4R)-1-acétyl-4-hydroxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[1-(anilinocarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(4-éthyl-1-méthylpipérazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-{1-[(1-oxydopyridin-2-yl)carbonyl]pyrrolidin-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(4R)-3-acétyl-1,3-thiazolidin-4-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-[1-méthyl-4-(méthylsulfonyl)pipérazin-2-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(4-méthylthiomorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-[4-fluoro-2-(méthylsulfonyl)benzyl]-5-hydroxy-1-méthyl-6-oxo-2-[1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-acétylpyrrolidin-2-yl)-N-[4-fluoro-2-(méthylsulfonyl)benzyl]-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(3-acétyl-1,3-thiazolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[1-(acétylamino)-1-méthyléthyl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-acétylpyrrolidin-2-yl)-N-(2-éthoxybenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(4-acétyl-1-méthylpipérazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-[1-méthyl-4-(pyrazin-2-ylcarbonyl)pipérazin-2-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-acétylpyrrolidin-2-yl)-5-hydroxy-1-méthyl-N-[2-(méthylthio)benzyl]-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-2-{1-[(1H-imidazol-5-ylcarbonyl)amino]-1-méthyléthyl}-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[1-benzoyl-4-(pyrazin-2-ylcarbonyl)pipérazin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(4-benzoyl-1-méthylpipérazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[4-(benzyloxy)-1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-acétylpyrrolidin-2-yl)-N-(2,3-diméthoxybenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-(1-acétylpyrrolidin-2-yl)-5-hydroxy-N-(2-méthoxybenzyl)-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-méthyléthyl]-N2,N2-diméthyléthanediamine ;
    2-(1-acétylpyrrolidin-2-yl)-N-[2-(diméthylamino)benzyl]-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2S)-1-acétylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-2-[4-hydroxy-1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-méthyléthyl]imidazo[2,1-b][1,3]thiazole-6-carboxamide ;
    2-[(2S,4S)-1-acétyl-4-fluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-{1-méthyl-4-[(1-méthyl-1H-imidazol-2-yl)carbonyl]pipérazin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(1-méthyl-1-{[(5-méthyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}éthyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N1-{1-[4-({[4-fluoro-2-(méthylsulfonyl)benzyl]amino}carbonyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1-méthyléthyl}-N2,N2-diméthyléthanediamide ;
    2-(4-acétyl-1,2-diméthylpipérazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyritnidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[1-(pyrimidin-4-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[1-(pyrimidin-5-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide ;
    N- (4-fluorobenzyl)-5-hydroxy-1-méthyl-2-{1-méthyl-1- [(1H-pyrazol-5-ylcarbonyl)amino]éthyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2R,4R)-1-acétyl-4-méthoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{1-[(diméthylamino)(oxo)acétyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-{1-[4-({[4-fluoro-2-(méthylsulfonyl)benzyl]amino}-carbonyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1-méthyléthyl}imidazo[2,1-b][1,3]thiazole-6-carboxamide ;
    2-[(2R,4R)-1-benzoyl-4-méthoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-2-[4-(isopropylsulfonyl)-1-méthylpipérazin-2-yl]-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[1,2-diméthyl-4-(méthylsulfonyl)pipérazin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;
    N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)-4-méthoxy-1-méthylpyrrolidin-2-yl]-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-{1-[(méthylsulfonyl)acétyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2S)-1-acétyl-4,4-difluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2R,4R)-1-acétyl-4-éthoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2S)-4,4-difluoro-1-méthylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(2,3-diméthoxybenzyl)-5-hydroxy-1-méthyl-6-oxo-2-[1-(pyridazin-3-ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-(1-méthyl-1-{[morpholin-4-yl(oxo)acétyl]amino}éthyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{(2R,4R)-1-[(diméthylamino)(oxo)acétyl]-4-méthoxypyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2S)-4,4-difluoro-1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-{(2S,4S)-1-méthyl-4-[(méthylsulfonyl)amino]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{1-[(diméthylamino)sulfonyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{(2R,4R)-4-éthoxy-1-[(méthylamino)(oxo)acétyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-[(2S)-4,4-difluoro-1-(pyridazin-3-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;
    2-[(2S)-4,4-difluoro-1-(pyrridin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{(2S)-1-[(diméthylamino)(oxo)acétyl]-4,4-difluoropyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-2-{1-[morpholin-4-yl(oxo)acétyl]pyrrolidin-2-yl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{(2S)-1-[(diméthylamino)(oxo)acétyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{(2S)-1-[(diméthylamino)(oxo)acétyl]pyrrolidin-2-yl}-N-(4-fluoro-2-méthoxybenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-méthyléthyl]-N1,N2,N2-triméthyléthanediamide ;
    2-[(2S)-1-acétylpyrrolidin-2-yl]-N-(4-fluoro-2-méthoxybenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N-(4-fluorobenzyl)-2-[(2S,4S)-4-fluoro-1-méthylpyrrolidin-2-yl]-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    2-{(2S,4S)-1-[(diméthylamino)(oxo)acétyl]-4-fluoropyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ;
    N1-[1-(4-{[(3-chloro-4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-méthyléthyl]-N2,N2-diméthyléthanediamide ;
    et leurs sels pharmaceutiquement acceptables.
  29. Composition pharmaceutique comprenant une quantité thérapeutiquement efficace d'un composé selon l'un quelconque des revendications précédentes, de l'un de ses sels pharmaceutiquement acceptable et un support pharmaceutiquement acceptable.
  30. Combinaison utile pour traiter ou prévenir une infection par le VIH ou pour prévenir, traiter ou retarder un déclenchement du SIDA, qui est une quantité thérapeutiquement efficace d'un composé selon l'une quelconque des revendications 1 à 28, ou de l'un de leurs sels pharmaceutiquement acceptables et une quantité thérapeutiquement efficace d'un antiviral choisi dans l'ensemble consistant en inhibiteurs de protéases de VIH, inhibiteur de transcriptase inverse du VIH non nucléosidiques et inhibiteurs de transcriptase inverse de VIH nucléosidiques.
  31. Composé selon l'une quelconque des revendications 1 à 28, ou un sel pharmaceutiquement acceptable de celui-ci, pour une utilisation dans un procédé de traitement de l'organisme humain par thérapie.
  32. Utilisation d'un composé selon l'une quelconque des revendications 1 à 28, ou d'un de ses sels pharmaceutiquement acceptables, pour la fabrication d'un médicament destiné à prévenir, traiter ou retarder le déclenchement du SIDA, ou pour le traitement ou la prévention d'une infection par le VIH.
  33. Composé selon la revendication 1 dans qui est le N 1-[1-(4-{[(9-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-méthyléthyl-N 2,N 2-diméthyléthanediamide ou l'un de ses sels pharmaceutiquement acceptables.
  34. Composé de la revendication 1 qui est le N-(4-fluorobenzyl)5-hydroxy-1-méthyl-2-(1-méthyl-1-{[(5-méthyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}éthyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide ou l'un de ses sels pharmaceutiquement acceptables.
  35. Composition pharmaceutique comprenant le composé de la revendication 33 ou 34, ou l'un de ses sels pharmaceutiquement acceptables et un support pharmaceutiquement acceptable.
  36. Composé de la revendication 33 ou 34, ou sel pharmaceutiquement acceptable de celui-ci, pour une utilisation dans un procédé de traitement de l'organisme humain par thérapie.
  37. Utilisation d'un composé de la revendication 33 ou 34, ou d'un de ses sels pharmaceutiquement acceptables pour la fabrication d'un médicament pour prévenir ou traiter une infection par le VIH ou prévenir, traiter ou retarder le déclenchement du SIDA.
  38. Combinaison utile pour le traitement ou la prévention d'une infection par le VIH, ou pour la prévention, le traitement ou le retard du déclenchement du SIDA, qui est une quantité thérpeutiquement efficace d'un composé selon l'une quelconque des revendications 33 ou 34, ou d'un de ses sels pharmaceutiquement acceptables, et une quantité thérapeutiquement efficace d'un antiviral choisi dans l'ensemble consistant en inhibiteurs de protéases du VIH, inhibiteurs de transcriptases inverses du VIH non nucléosidiques et inhibiteurs de transcriptases inverses du VIH nucléosidiques.
  39. Combinaison de la revendication 38, dans laquelle l'antiviral est choisi parmi les abacavir, abacavir + lamivudine + zidovudine, acemannane, ACH 126443, acyclovir, AD-439, AD-519, adefovir dipivoxil, AL-721, interféron alpha, AMD3100, amprénavir, ansamycine, un anticorps qui neutralise un interféron alpha aberrant labile au pH, AR177, atazanavir, bêta-fluoro-ddA, BMS-232623, BMS-234475, capravirine, CI-1012, cidofovir, sulfate de curdlan, immunoglobine de cytomégalovirus, ganciclovir, delavirdine, sulfate de dextran, didésoxycytidine, didésoxyinosine, DPC 681, & DPC 684, DPC 961 & DPC 083, EL10, efavirenz, famciclovir, emtricitabine, emvirine, HBY097, hypericine, interféron bêta humain recombinant, interféron alpha-n3, indinavir, ISIS 2922, JB2147/AG1776, KNI-272, lamivudine, lobucavir, lopinavir, lopinavir + ritonavir, mozenavir, nelfinavir, névirapine, novapren, pentafusaïde, séquence octapeptidique de peptide T, PRO 542, PRO 140, phosphonoformate trisodique, PNU-140690, probucol, RBC-CD4, ritonavir, saquinavir, stavudine, T-1249, TAK-779, tipranavir, TMC-120 & TMC-125, TMC-126, valaciclovir, ribavarine et zidovudine.
EP02801950A 2001-10-26 2002-10-21 Inhibiteurs de l'integrase du vih a base d'hydroxypyrimidinone carboxamide n-substitue Expired - Lifetime EP1441735B1 (fr)

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ME00427B (me) 2011-10-10
US20050025774A1 (en) 2005-02-03
CN1700918B (zh) 2011-06-08
DE60209381T2 (de) 2006-10-05
NL300340I2 (nl) 2008-08-01
EA007060B1 (ru) 2006-06-30
EP1441735A1 (fr) 2004-08-04
CN1700918A (zh) 2005-11-23
US7217713B2 (en) 2007-05-15
DK1441735T3 (da) 2006-06-12
BR0213522B8 (pt) 2017-07-04
US7435734B2 (en) 2008-10-14
EA200400585A1 (ru) 2004-10-28
IL161337A (en) 2010-02-17
JP2005511543A (ja) 2005-04-28
HRP20040373A2 (en) 2005-08-31
IS2436B (is) 2008-10-15
CN102219750A (zh) 2011-10-19
NO20042165L (no) 2004-05-25
DE122008000016I1 (de) 2011-12-01
CA2463976A1 (fr) 2003-05-01
BRPI0213522C1 (pt) 2021-05-25
HK1085665A1 (en) 2006-09-01
US7169780B2 (en) 2007-01-30
KR20040047981A (ko) 2004-06-05
CY2008008I1 (el) 2009-11-04
ZA200402796B (en) 2005-03-30
YU35604A (sh) 2006-08-17
HUP0401740A3 (en) 2009-06-29
ATE318140T1 (de) 2006-03-15
DE60209381D1 (de) 2006-04-27
NO2008007I2 (fr) 2010-09-27
AU2002334207B2 (en) 2006-02-23
JP3927175B2 (ja) 2007-06-06
GEP20063848B (en) 2006-06-12
IS7213A (is) 2004-04-07
ES2258668T3 (es) 2006-09-01
LU91428I2 (fr) 2008-06-09
CA2463976C (fr) 2007-02-13
CN102229605B (zh) 2015-01-14
LTC1441735I2 (lt) 2020-06-25
DE122009000048I1 (de) 2010-04-08
WO2003035077A1 (fr) 2003-05-01
RS51542B (sr) 2011-06-30
NZ533057A (en) 2005-11-25
NO2020026I1 (no) 2020-08-10
NO325206B1 (no) 2008-02-25
US20080275004A1 (en) 2008-11-06
US20110034449A1 (en) 2011-02-10
US20070123524A1 (en) 2007-05-31
IL161337A0 (en) 2004-09-27
UA77454C2 (en) 2006-12-15
LTPA2008007I1 (lt) 2020-05-11
FR08C0026I1 (fr) 2008-07-18
CN102219750B (zh) 2013-05-29
CN102229605A (zh) 2011-11-02
KR100862879B1 (ko) 2008-10-15
US7820660B2 (en) 2010-10-26
NL300340I1 (nl) 2008-06-02
FR08C0026I2 (fr) 2010-01-22
NO2008007I1 (no) 2008-06-23
HU230248B1 (hu) 2015-11-30
PL369223A1 (en) 2005-04-18
PL212914B1 (pl) 2012-12-31
MXPA04003932A (es) 2004-06-18
HUS1600016I1 (hu) 2018-05-02
SI1441735T1 (sl) 2006-06-30
HUP0401740A2 (hu) 2004-12-28
HRP20040373B1 (en) 2012-09-30
BR0213522A (pt) 2004-09-08
CO5580777A2 (es) 2005-11-30
US20060258860A1 (en) 2006-11-16
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